RU2445309C2 - Tyrosine kinase inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I)

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R₂ represents lower alkyl substituted by one or more identical or different radicals R₃, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R₃ is specified in the patent claim, or R₁ and R₂ together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R₄ represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

Description

The invention relates to new substituted pyrimidinylaminobenzamides, methods for their preparation, pharmaceutical compositions containing them, their use optionally in combination with one or more other pharmaceutically active compounds for treating a disease that is associated with inhibition of protein kinase activity, especially a tumorous disease, in particular leukemia, and a method treatment of such a disease.

State of the art

Protein kinases (PK) are enzymes that catalyze the phosphorylation of specific serine, threonine or tyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switches that regulate cell proliferation, activation and / or differentiation. Abnormal or excessive PK activity is observed for many diseases, including benign and malignant proliferative diseases. In some cases, the cure of diseases, such as proliferative diseases, is possible due to the use of PK inhibitors in vitro and in vivo.

In view of the large number of protein kinase inhibitors and the many proliferative and other PK-related diseases, there is still a need for new classes of compounds that will be useful as PK inhibitors and therefore for the treatment of these PTK-related diseases. This is provided by new classes of pharmaceutically useful PK inhibitory compounds.

The Philadelphia chromosome is a sign of chronic myelogenous leukemia (CML) and carries a hybrid gene that contains the N-terminal exons of the bcr gene and the main C-terminal part (exons 2-11) of the c-abl gene. The gene product is a 210 kDa protein (p210 Bcr-Abl). The Abl portion of the Bcr-Abl protein contains abl-tyrosine kinase, which is highly regulated by wild-type c-abl, but is initially activated in the Bcr-Abl fusion protein. This unregulated tyrosine kinase interacts with numerous cellular signals, leading to transformation and impaired regulation of cell proliferation (Lugo et al., Science 247, 1079 [1990]).

General Description of the Invention

It has been found that various compounds of the pyrimidinylaminobenzamide class exhibit inhibition of protein kinase activity. The compounds of formula I, described in more detail below, especially exhibit inhibition of one or more tyrosine kinases, such as c-Abl, Bcr-Abl, the tyrosine kinase receptor PDGF-RFlt3, VEGF-R, EGF-R and c-Kit, as well as combinations of two or several of them; in the case of the novel pyrimidinylaminobenzamides according to the invention, the compounds are suitable for inhibiting these and / or other protein kinases, especially the protein kinases mentioned above, and / or for inhibiting mutants of these enzymes, especially Bcr-Abl, for example, the Glu255 -> valine mutant. Due to this activity, the compounds can be used to treat diseases associated especially with abnormal or excessive activity of these types of kinases, especially those mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a compound of formula I

Where

R ₁ represents hydrogen, lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl or phenyl lower alkyl;

R ₂ represents hydrogen, lower alkyl, optionally substituted with one or more identical or different radicals R ₃ , cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, where the groups in each case are unsubstituted or mono- or polysubstituted;

and R ₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group or a mono- or bicyclic a heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, where the groups in each case are unsubstituted or mono- or polysubstituted;

or where R ₁ and R ₂ together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen atom and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms, where the nitrogen atom is unsubstituted or substituted with lower alkyl, phenyl lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, N-mono or N N-disubstituted with carbamoyl lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R ₄ represents hydrogen, lower alkyl or halogen;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

Used hereinafter, the general terms in the context of this description have, preferably, the following meanings, unless otherwise indicated.

The term "lower" means a radical having inclusively up to 7, especially inclusive up to 4 carbon atoms, these radicals are linear or branched with one or more branches.

When using the plural form of the compound, salt, etc. it also denotes the singular form of a compound, salt or the like.

Any asymmetric carbon atoms may be present in the (R) -, (S) - or (R, S) configuration, preferably in the (R) - or (S) configuration. The compounds may thus be present as a mixture of isomers or as pure isomers, preferably as enantiomerically pure diastereomers.

The invention also relates to possible tautomers of compounds of formula I.

Lower alkyl is preferably alkyl with 1-7 inclusive, preferably 1-4 inclusive carbon atoms, and is linear or branched; preferably lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably, lower alkyl is methyl, propyl or tert-butyl.

Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.

An aryl group is an aromatic radical that is attached to a molecule through a bond with the carbon atom of the aromatic ring of this radical. In a preferred embodiment, aryl is an aromatic radical having 6-14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, esterified hydroxy, nitro, cyano, carboxy, ether cited or esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylsilyl-vinyl, , phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkyl mercapto, halogen-lower alkylsulfonyl, such as especially trifluorome ethanesulfonyl, dihydroxyboron (-B (OH) ₂ ), heterocyclyl and lower alkylene-dioxi-bonded on adjacent C-atoms of the ring, such as methylenedioxy. Aryl is most preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case are unsubstituted or independently substituted with one or two substituents selected from the group consisting of halogen, especially fluorine, chlorine or bromine; hydroxy; hydroxy esterified with lower alkyl, for example methyl, halogen lower alkyl, for example trifluoromethyl, or phenyl; lower alkylene-dioxo-bonded to two adjacent C-atoms, for example methylenedioxy, lower alkyl, for example methyl or propyl; halogen lower alkyl, for example trifluoromethyl; hydroxy lower alkyl, for example hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy lower alkyl; for example methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl lower alkyl, for example methoxycarbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl, for example methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-mono-substituted carbamoyl, in particular carbamoyl, monosubstituted with lower alkyl, for example methyl, n-propyl or isopropyl; amino; lower alkylamino, for example methylamino; lower alkylamino, for example dimethylamino or diethylamino; lower alkylene amino, for example pyrrolidino or piperidino; lower oxaalkylene-amino, for example morpholino, lower azaalkylene-amino, for example piperazino, acylamino, for example acetylamino or benzoylamino; lower alkylsulfonyl, for example methylsulfonyl; sulfamoyl; or phenylsulfonyl.

The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl and may be unsubstituted or substituted with one or more, especially one or two, substituents selected from the group defined above for aryl substituents, most preferably lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and also oxo, or is fused to the benzene ring, as in benzcyclopentyl or benzcyclohexyl.

Substituted alkyl is alkyl, as defined above, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N, N-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl lower alkoxycarbonyl. Trifluoromethyl is particularly preferred.

The mono- or disubstituted amino is especially amino substituted with one or two radicals independently selected from lower alkyl, such as methyl; hydroxy lower alkyl such as 2-hydroxyethyl; phenyl lower alkyl such as benzyl or 2-phenylethyl; lower alkanoyl such as acetyl; benzoyl; substituted benzoyl, where the phenyl radical is, in particular, substituted by one or more, preferably one or two substituents selected from nitro, amino, halogen, N-lower alkylamino, N, N-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl lower alkanoyl and carbamoyl; and phenyl lower alkoxycarbonyl, where the phenyl radical is unsubstituted or especially substituted with one or more, preferably one or two substituents selected from nitro, amino, halogen, N-lower alkylamino, N, N-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and carbamoyl; and preferably is N-lower alkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as 2-hydroxyethylamino, phenyl-lower alkylamino, such as benzylamino, N, N-lowering alkylamino, N-phenyl-lower alkyl -N-lower alkylamino, N, N-lowering alkylphenylamino, lower alkanoylamino, such as acetylamino, or a substituent selected from the group consisting of benzoylamino and phenyl lower alkoxycarbonylamino, where the phenyl radical in each case is unsubstituted or especially substituted nitro or amino, or also a halogen nom, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino. The disubstituted amino is also lower alkylene-amino, for example pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkyleneamino, for example morpholino, or lower azaalkyleneamino, for example piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.

Halogen is especially fluoro, chloro, bromo, or iodo, especially fluoro, chloro or bromo.

The esterified hydroxy is especially C ₈ -C ₂₀ alkyloxy, such as n-decyloxy, lower alkoxy (preferably), such as methoxy, ethoxy, isopropyloxy or tert-butyloxy, phenyl lower alkoxy, such as benzyloxy, phenyloxy, or halo- lower alkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy.

The esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy such as tert-butoxycarbonyloxy or phenyl lower alkoxycarbonyloxy such as benzyloxycarbonyloxy.

The esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl lower alkoxycarbonyl or phenyloxycarbonyl.

Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, for example acetyl.

N-Mono- or N, N-disubstituted carbamoyl is particularly substituted with one or two substituents independently selected from lower alkyl, phenyl lower alkyl and hydroxy lower alkyl, or lower alkylene, oxa lower alkylene or aza lower alkylene, optionally substituted on the final nitrogen atom.

A mono- or bicyclic heteroaryl group comprising zero, one, two or three nitrogen atoms in the ring and zero or one oxygen atom and zero or one sulfur atom, where the groups in each case are unsubstituted or mono- or polysubstituted, means a heterocyclic group which is unsaturated in the ring linking the heteroaryl radical to the remainder of the molecule of formula I, and is preferably a ring in the linking ring, but optionally also in any nonlinear ring, at least one carbon atom is substituted a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the connecting ring preferably has 5-12, most preferably 5 or 6 atoms in the ring; and which may be unsubstituted or substituted by one or more, especially one or two substituents selected from the group defined above for aryl substituents, most preferably lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy. Preferably, the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolisinyl, isoquinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolininyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinolinyl quinilinolininyl quinolinol in the , pteridinyl, indolisinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanil, benzo [d] pyrazolyl, thienyl and furanyl. Most preferably, the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3 - or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo [d] pyrazolyl, thienyl and furanyl . In one preferred embodiment of the invention, the pyridyl radical is substituted with hydroxy in the ortho position to the nitrogen atom and, therefore, exists, at least partially, in the form of the corresponding tautomer, which is pyridin- (1H) 2-one. In another preferred embodiment, the pyrimidinyl radical is substituted with hydroxy at positions 2 and 4 and, therefore, exists in several tautomeric forms, for example, in the form of pyrimidine- (1H, 3H) 2,4-dione.

Heterocyclyl is especially a five-, six- or seven-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, and is unsubstituted or substituted with especially lower alkyl, such as methyl, phenyl lower alkyl, such as benzyl, oxo or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, 4-piperidinyl, N-benzyl-4-piperidinyl, 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl or 2-methyl-1,3-dioxolan-2-yl.

Salts are especially pharmaceutically acceptable salts of the compounds of formula I.

Such salts are obtained, for example, in the form of acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen-containing acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propanoic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleino hydrochloric acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 2-hydroxyethanesulfonic acid, 2-hydroxyethanesulfonic acid, 2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalendisulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethyl sulfuric acid, dodecylsulfuric acid Lot, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propilsulfamovaya acid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy or sulfo, salts can also be prepared with bases, for example salts with a metal or ammonium, such as salts with an alkali metal or alkaline earth metal, for example salts with sodium, potassium, magnesium or calcium, or ammonium salts with ammonium or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri (2-hydroxyethyl) amine, or heterocyclic bases, for example N-ethylpiperidine or N, N'-dimethylpiperazine.

When both the main group and the acid group are present in one molecule, the compound of formula I can also form internal salts.

Pharmaceutically unacceptable salts, such as picrates or perchlorates, may also be used to isolate or purify. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where appropriate in the form of pharmaceutical formulations) are used, and they are therefore preferred.

Due to the proximity of new compounds in free form and compounds in the form of their salts, including salts that can be used as intermediates, for example, in the purification or identification of new compounds, any reference to compounds in free form hereinafter should be understood as indicating also corresponding salts, where appropriate and appropriate.

The compounds of formula I and their N-oxides have valuable pharmacological properties, as described hereinafter.

The effectiveness of the compounds of the invention as inhibitors of the activity of c-Abl, Bcr-Abl and VEGF receptors of tyrosine kinase can be determined as follows.

Test for activity against c-Abl protein tyrosine kinase. The test was performed as a binding test as follows: His-labeled c-Abl kinase domain was cloned and expressed in the baculovirus / Sf9 system as described by Bhat et al., J Biol Chem. 272, 16170-5 (1997). The 37 kDa protein (c-Abl kinase) was purified by a two-step method on a column of cobalt chelate and then on an anion exchange column with a yield of 1-2 mg / L Sf9 cells. The purity of c-Abl kinase was> 90%, as determined by SDS-PAGE after staining with Cumach blue. The test contains: c-Abl kinase (50 ng), 20 mm Tris-HCl, pH 7.5, 10 mm MgCl ₂ , 10 μm Na ₃ VO ₄ , 1 mm DTT and 0.06 μ Ci / test [γ ³³ P ] -ATP (5 μM ATP) with 30 μg / ml poly-Ala, Glu, Lys, Tyr - 6: 2: 5: 1 (Poly-AEKY, Sigma P1152) in the presence of 1% DMSO, total volume 30 μl. Reactions were stopped by the addition of 10 μl of 250 mM EDTA and 30 μl of the reaction mixture was transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA), pre-impregnated with methanol for 5 min, washed with water, then 0.5% impregnated for 5 min H ₃ PO ₄ and mounted on a vacuum manifold with an unconnected vacuum source. After determining all samples, a vacuum was connected and each well was washed with 200 μl of 0.5% H ₃ PO ₄ . Membranes were removed and washed on a stirrer with 0.5% H ₃ PO ₄ (4 times) and once with ethanol. Membranes were quantitated after drying at ambient temperature by installing a 96-cell frame in Packard TopCount and adding 10 μl / well of MicroscintTM (Packard).

Activity test against Bcr-Abl. The 32Dcl3 muscle myeloid progenitor cell line transfected with the p210 Bcr-Abl expression vector pGDp210Bcr / Abl (32D-bcr / abl) was obtained from J. Griffin (Dana Faber Cancer Institue, Bosten, MA, USA). The cells express the fusion Bcr-Abl protein with initially active abl kinase and proliferate growth factor independently. Cells were expanded in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) (“complete medium”), and stock was prepared by freezing aliquots of 2 × 10 ⁶ cells per vessel in a freezing medium (95% FCS, 5 % DMSO (SIGMA)). After thawing, the cells were used for a maximum of 10-12 times in the experiments.

For cell testing, the compounds were dissolved in DMSO and diluted with complete medium to obtain an initial concentration of 10 μM, followed by 3-fold serial dilutions in complete medium. 200,000 32D-Bcr / Abl cells in 50 μl of complete medium were plated on 96-well round-bottom tissue culture substrates. Three times 50 μl per well of 3-fold serial dilutions of the test compound were added to the cells. Untreated cells were used as a control. The compound was incubated with the cells for 90 min at 37 ° C, 5% CO ₂ , followed by centrifugation of the tissue culture substrates at 1300 rpm (Beckmann GPR centrifuge) and the supernatants removed by thorough blowing so as not to destroy the destroyed cells. Cell residues were lysed by adding 150 μl of lysis buffer (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF , 50 μg / ml aprotinin and 80 μg / ml leupeptin) and were immediately used for ELISA or stored frozen in substrates at -20 ° C until use. Black ELISA substrates (Packard HTRF-96 black substrates) were pretreated overnight at 4 ° C. with 50 ng / well of the rabbit polyclonal anti-abl-SH3 domain Ab 06-466 from Upstate in 50 μl PBS. After washing 3 times with 200 μl / well of PBS containing 0.05% Tween20 (PBST) and 0.5% TopBlock (Juro), the remaining protein binding sites blocked 200 μl / well of PBST, 3% TopBlock for 4 hours at room temperature followed by incubation with 50 μl of lysates of untreated or compound-treated cells (20 μg of total protein per well) for 3-4 hours at 4 ° C. After 3 washes, 50 μl / well of anti-phosphothyrosine Ab PY20 (AP) labeled with alkaline phosphatase (Zymed) diluted to 0.2 μg / ml in blocking buffer was added and incubated overnight (4 ° C). For all incubation steps, the substrates were covered with lids (Costar). Finally, the substrates were washed three more times with wash buffer and once with deionized water before adding 90 μl / well of CDPStar RTU AP substrate with Emerald II. The substrates covered with Packard TopSeal ™ - substrate covers were incubated for 45 min at room temperature in the dark and the luminescence was measured by measurement per second (CPS) using the Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the ELISA reading (CPS) obtained for the lysate with untreated 32D-Bcr / Abl cells and the reading for the base test (all components, but without the cell lysate) was calculated and taken as 100% reflection of the initially phosphorylated Bcr-Abl protein, present in these cells. The activity of the compound relative to the Bcr-Abl kinase was expressed as a percentage of the decrease in phosphorylation of Bcr-Abl. The values of IC ₅₀ and IC _{90 were} determined from the curves of the dependence on the dose by graphical extrapolation.

Test for activity against VEGF-receptor tyrosine kinase. The test was performed using the Flt-1 VEGF tyrosine kinase receptor. A detailed procedure is as follows: 30 μl of a kinase solution (10 ng of the kinase domain of Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) in 20 mM Tris * HCl pH 7.5, 3 mM manganese dichloride (MnCl ₂ ), 3 mM magnesium chloride (MgCl ₂ ), 10 μM sodium vanadate, 0.25 mg / ml polyethylene glycol (PEG) 20,000, 1 mm dithiothreitol and 3 μg / ml poly (Glu, Tyr) 4: 1 (Sigma, Buchs , Switzerland), 8 μM [ ³³ P] -ATP (0.2 μCi), 1% DMSO and 0-100 μM test compound were incubated together for 10 minutes at room temperature. The reaction was then stopped by adding 10 μl of 0.25 M ethylenediaminetetraacetate (EDTA) pH 7. Using a multichannel dispenser (LAB SYSTEMS, USA), an aliquot of 20 μl was applied to the Immobilon P PVDF membrane (= polyvinyl difluoride) (Millipore, Bedford, USA) via Gibco-BRL microtiter pleated filter and associated with vacuum. After complete separation of the liquid, the membrane was washed 4 times in a bath containing 0.5% phosphoric acid (H ₃ PO ₄ ) and once with ethanol, incubated for 10 minutes each time with shaking, then mounted on a Hewlett Packard TopCount Manifold and the radioactivity was measured after adding 10 μl of Microscint ™ (liquid for B-stintillation counter). The IC ₅₀ values were determined by linear regression analysis of the percentage for inhibition of each compound in at least four concentrations (typically 0.01, 0.1, 1.0, and 10 μmol). The IC ₅₀ values that can be found for compounds of formula I are in the range of 1 to 10'000 nM, preferably in the range of 1 to 100 nM.

Inhibition of VEGF-induced KDR receptor autophosphorylation can also be confirmed by an in vitro experiment on cells: transfected CHO cells that continuously express the human VEGF receptor (KDR) were planted in complete culture medium with 10% fetal calf serum (FCS) in 6-cell substrates for cell culture and incubated at 37 ° C under 5% CO ₂ to 80% confluence. The test compounds were then diluted with culture medium (without FCS, with 0.1% bovine serum albumin) and added to the cells. (The controls contained medium without test compounds.) After two hours of incubation at 37 ° C, recombinant VEGF was added; the final concentration of VEGF was 20 ng / ml. After the next five minutes of incubation at 37 ° C, the cells were washed twice with ice-cold PBS (phosphate buffered saline) and immediately lysed in 100 μl of lysis buffer per well. The lysates were then centrifuged to remove cell nuclei and supernatant protein concentrations were determined using a commercial protein analysis (BIORAD). Then the lysates can be immediately used or, if necessary, stored at -20 ° C.

An ELISA sandwich was performed to measure KDR receptor phosphorylation: a monoclonal antibody for KDR (e.g., Mab 1495,12,14) was immobilized on black ELISA substrates (OptiPlate ™ HTRF-96 from Packard). The substrates were then washed and the remaining free protein binding sites were saturated with 1% BSA in PBS. Cell lysates (20 μg protein per well) were then incubated on these substrates overnight at 4 ° C. together with an alkaline phosphatase-bound antiphosphothyrosine antibody (PY20: AP from Transduction Laboratories). The substrates were washed again and then binding of the antiphosphothyrosine antibody to the captured phosphorylated receptor was determined using a luminescent AP substrate (CDP-Star, ready to use, with Emerald II; TROPIX). Luminescence was measured using a Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the positive control signal (stimulated by VEGF) and the negative control signal (not stimulated by VEGF) corresponds to the VEGF-induced KDR receptor phosphorylation (= 100%). The activity of the test substances was calculated as% inhibition of VEGF-induced KDR receptor phosphorylation, where the concentration of a substance that exhibited half of the maximum inhibition was determined as ED ₅₀ (effective dose for 50% inhibition). The compounds of formula I preferably exhibit ED ₅₀ values in the range of 0.25 nM to 1000 nM, preferably 0.25 to 250 nM.

The compound of formula I or its N-oxide also inhibits, to varying degrees, other tyrosine kinases involved in signaling mediated by trophic factors, for example, Bcr-Abl and Abl kinase, Arg, kinases from the Src family, especially c-Src kinase, Lck and Fyn ; also kinases of the EGF family, for example, c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth factor receptor kinase (IGF-1 kinase) kinase, especially members of the tyrosine kinase family of the PDGF receptor, such as PDGF receptor kinase, CSF-1 receptor kinase, Kit receptor kinase and VEGF receptor kinase; as well as serine / threonine kinases, each of which plays a role in regulating the growth and transformation of mammalian cells, including human cells.

The inhibition of c-erbB2 tyrosine kinase (HER-2) can be measured, for example, similarly to the inhibition of EGF-R protein kinase using known methods.

Based on these studies, the compound of formula I in accordance with the invention exhibits therapeutic efficacy especially against protein kinase-dependent diseases, especially proliferative diseases.

Based on their effectiveness as inhibitors of the VEGF receptor tyrosine kinase activity, the compounds of formula I primarily inhibit blood vessel growth and are thus, for example, effective against a variety of diseases associated with unregulated angiogenesis, especially diseases caused by ocular neovascularization, especially retinopathies, such as diabetic retinopathy or age spots, psoriasis, hemangioblastoma, such as hemangioma, proliferative diseases of mesangial cells, such as chronic or acute kidney diseases, for example, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, hemolytic-uremic syndrome, diabetic nephropenosis, arteriopathic nephropenosis, arteriopathic nephropenosis, arteriopathic nephropenosis, arteriopathic nephropenosis, arteriopathic nephropenosis, arteriosis, nephropenosis, and nephropenosis, nephropenosis, , diabetes, endometriosis, chronic asthma, and especially tumor diseases (solid tumors, as well as neukemia and other "liquid tumors", especially tumors expressing c-kit, KDR, Flt-1 or Flt-3), such as especially breast cancer, colon cancer, lung cancer (especially cancer of small lung cells), prostate cancer or Kaposi's sarcoma. The compound of formula I (or its N-oxide) inhibits tumor growth and is particularly suitable for preventing the spread of metastatic tumors and the growth of micrometastases.

A compound of formula I may be administered alone or in combination with one or more other therapeutic agents, a possible combination therapy takes the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents administered or taken independently, or the combined administration of fixed combinations and one or more other therapeutic agents. The compound of formula I can also be administered especially for the treatment of a tumor, such as in the treatment of leukemia, in combination with chemotherapy, radiotherapy, immunotherapy, surgery or a combination thereof. Both long-term therapy and adjuvant therapy with other treatment methods are equally possible, as described above. Other possible treatments are therapy to maintain the patient's condition after tumor regression or even chemotherapy, for example, in patients at risk.

The therapeutic agents for the possible combination are especially one or more cytostatic or cytotoxic compounds, for example, a chemotherapeutic agent or agents selected from the group consisting of indarubicin, cytarubicin, interferon, hydroxyurea, bisulfan or a polyamine biosynthesis inhibitor, a protein kinase inhibitor, especially a serine / threonine protein like protein kinase C, or tyrosine protein kinase, such as epidermal growth factor receptor tyrosine kinase, cytokine, negative regulation a growth promoter such as TGF-β or IFN-β, an aromatase inhibitor, a classic cytostatic agent, and an inhibitor of the interaction of the SH2 domain with a phosphorylated protein.

The compound of the invention is useful not only for (prophylactic and preferably therapeutic) administration to humans, but also for the treatment of other warm-blooded animals, for example industrially useful animals, for example rodents such as mice, rabbits or rats, or guinea pigs. Such a compound can also be used as a reference standard in the test systems described above for comparison with other compounds.

In general, the invention also relates to the use of a compound of formula I or its N-oxide for inhibiting tyrosine kinase activity, in vitro or in vivo.

In the groups of the preferred compounds of the formula I mentioned below and their N-oxides, the definitions of substituents from the general definitions mentioned above can be used successfully, for example, to replace more general definitions with more specific definitions or particularly preferred definitions.

In particular, the invention relates to compounds of formula I, where

R ₁ represents hydrogen, lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl or phenyl lower alkyl;

R ₂ represents hydrogen, lower alkyl, optionally substituted with one or two identical or different radicals R ₃ , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group or a mono- or bicyclic heteroaryl group containing one, two or three nitrogen atoms or one sulfur atom, where the aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;

and R ₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, furanoyl, thienoyl or a mono- or bicyclic heteroaryl group comprising one, two or three nitrogen atoms in the ring, zero or one oxygen atom in the ring and zero or one sulfur atom in the ring, where the aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;

or where R ₁ and R ₂ together are alkylene with four or five carbon atoms, optionally mono- or disubstituted with lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl ; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen atom and three or four carbon atoms, or azaalkylene with one nitrogen atom and three or four carbon atoms, where nitrogen is unsubstituted or substituted by lower alkyl, phenyl lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, N-mono- or N, N-disubstituted with carbamoyl lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R ₄ represents hydrogen, lower alkyl or halogen;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

More specifically, the invention relates to compounds of formula I, where

R ₁ represents hydrogen, lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl or phenyl lower alkyl;

R ₂ is hydrogen, lower alkyl, optionally substituted with one or two identical or different radicals R ₃ , cyclopentyl, benzcyclopentyl, cyclohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxoazepinyl, oxazepinyl vinyl, phenyl tetrahydronaphthalenyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, where the phenyl, naphthalenyl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted, yl or lower alkoxycarbonyl-lower alkiltienil;

and R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N- phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalenyl, tetrahydronaphthalenyl, or a mono- or bicyclic heteroaryl group containing one or two heteroarynyl and nitroenyl groups, where single or mono-or polysubstituted;

or where R ₁ and R ₂ together are alkylene with four or five carbon atoms, optionally mono- or disubstituted with lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl ; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen atom and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, N-mono- or N, N- disubstituted with carbamoyl lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R ₄ represents hydrogen, lower alkyl or halogen;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

More specifically, the invention relates to compounds of formula I, where

R ₁ represents hydrogen, lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl or phenyl lower alkyl;

R ₂ represents hydrogen; lower alkyl optionally substituted with one R ₃ radical, two phenyl groups, two lower alkoxycarbonyl groups, phenyl and lower alkoxycarbonyl or hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cyclohexyl; pyrrolidinyl; oxazolinyl; piperidinyl; N-lower alkyl piperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxoazepinyl; oxazepinyl; phenyl, naphthalenyl, tetrahydronaphthalenyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, where the phenyl, naphthalenyl and heteroaryl groups in each case are unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro- lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, lower alkylamino lower alkyl, N-cyclohexyl-N-lower alkylamino lower alkyl, n lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxycarboxyloxycarboxyloxycarboxyloxy, benzoyloxy, alkyl carbamoyl, amino, lower alkanoylamino, benzoylamino, amino, mono- or disubstituted with lower alkyl, hydroxy lower alkyl or lower alkoxy lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piper but, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, phenyl, pyridyl, benzoyl, or halogen; thienyl or lower alkoxycarbonyl lower alkylthienyl;

and R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl, mono- or disubstituted by lower alkyl, phenyl or lower alkylene, amino, lower alkylamino, lower alkylamino, phenylamino, N-lower alkyl-N- phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl; phenyl, naphthalenyl, tetrahydronaphthalenyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, where the phenyl, naphthalenyl and heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl lower alkyl, hydroxy, lower alkoxy, trifluoro lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamine o, amino, mono- or disubstituted with lower alkyl, hydroxy lower alkyl or lower alkoxy lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl-alkylamide, 1 -1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, halogenyl or benzoyl;

or where R ₁ and R ₂ together are alkylene with four or five carbon atoms, optionally mono- or disubstituted with lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamino, piperidino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen atom and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms, where the nitrogen is unsubstituted or substituted by lower alkyl, phenyl lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, carbamoyl lower alkyl, N-mono or N, N-disubstituted lower alkyl, phenyl, lower alkylene or oxa-lower alkylene, cycloalkyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R ₄ represents hydrogen or lower alkyl;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

In a preferred group of compounds of formula I

R ₁ represents hydrogen, lower alkyl, lower alkoxy lower alkyl or benzyl;

R ₂ is lower alkyl, optionally substituted with one R ₃ radical, two phenyl groups, two lower alkoxycarbonyl groups, phenyl and lower alkoxycarbonyl or hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cyclohexyl; pyrrolidinyl; piperidinyl; N-lower alkyl piperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxoazepinyl; phenyl; naphthalenyl; tetrahydronaphthalenyl; pyridyl; lower alkyl pyridyl; quinolinyl; thienyl; lower alkoxycarbonylmethylthienyl or phenyl substituted with one or two substituents selected from the group consisting of lower alkyl, trifluoro lower alkyl, hydroxy lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, lower alkylamino lower alkyl, N-cyclohexyl -N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy higher alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino, mono- or disubstituted with lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl, 1H-imide -imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkyl piperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogen or benzoyl;

and R ₃ is hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, piperidino, , oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalenyl, tetrahydronaphthalenyl, furyl, a mono- or bicyclic heteroaryl group containing one or two nitrogen atoms, where the heteroaryl group is unsubstituted or mo but- or disubstituted with lower alkyl, hydroxy and lower alkoxy, or phenyl substituted with one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy , lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino, mono- or disubstituted with lower alkyl, hydroxy lower alkyl or lower alkoxy lower alkyl, pyrrolidino, piperidino, mor Ohlin piperazino, N-lower alkylpiperazino, N-lower alkoksikarbonilpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, halogen, or benzoyl;

or where R ₁ and R ₂ together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted with phenyl, hydroxy, amino, benzoylamino or piperidino; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen atom and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms, where the nitrogen is unsubstituted or substituted with lower alkyl, phenyl lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, pyrrolidinocarbonyl lower alkyl, morpholinocarbonyl lower alkyl, cyclopentoxycarbonyl lower alkyl phenyl, methoxyphenyl, trifluoromethylphenyl, pyridinyl, pyrimidinyl or pyrazinyl;

R ₄ represents hydrogen or methyl;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

A particularly preferred group of compounds includes compounds of formula I, where

R ₁ represents hydrogen and

R ₂ is phenyl substituted with trifluoromethyl, especially 3-trifluoromethylphenyl, and optionally also having a substituent selected from the group consisting of hydroxy lower alkyl, for example 1-hydroxy-1-methylethyl, lower alkylamino, for example methyl or ethylamino, hydroxy lower alkylamino, for example 2-hydroxy-1-propylamino or 2-hydroxy-2-propylamino, lower alkylamino, for example diethylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, for example 2- or 4-methyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbam yl, pyrrolidino, piperidino, piperazino, lower alkyl piperazino, for example 4-methylpiperazino, morpholino, lower alkoxy, for example methoxy, lower alkoxy fluorine, for example trifluoromethoxy or 2,2,2-trifluoroethoxy, phenyl, pyridyl, for example 2-, 3- or 4-pyridyl and halogen, for example chlorine or fluorine;

R ₄ represents methyl;

and an N-oxide or pharmaceutically acceptable salt of such a compound.

Particularly preferred are the compounds described in the examples.

Other compounds that are particularly preferred are:

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzanilide,

4-methyl-N- (3-pyridinyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- (4-chlorophenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

2 (R) - and 2 (S) - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoylamino] propanoic acid,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (8-quinolinyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (3- [trifluoromethoxy] phenyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (2-pyrrolidinoethyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (3-pyrrolidinophenyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (1- [2-pyrimidinyl] -4-piperidinyl) benzamide,

N- (4-di- [2-methoxyethyl] amino-3-trifluoromethylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- (4- [1H-imidazolyl] -3-trifluoromethylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (2-pyrrolidino-5-trifluoromethylphenyl) benzamide,

N- (3,4-difluorophenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (3-trifluoromethylbenzyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (3-trifluoromethylphenyl) benzamide,

N- (3-chloro-5-trifluoromethylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- (4-dimethylaminobutyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- [4- (4-methyl-1-piperazinyl) -3-trifluoromethylphenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (2,2,2-trifluoroethoxy) -3-trifluoromethylphenyl] benzamide,

4-methyl-N- [4- (2-methyl-1H-imidazolyl) -3-trifluoromethylphenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- (4-phenyl-3-trifluoromethylphenyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- [4- (4-methyl-1H-imidazolyl) -3-trifluoromethylphenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

methyl 2 (R) - and 2 (S) - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoylamino] -3- [4-hydroxyphenyl] propanoate,

N- [2- (N-cyclohexyl-N-methylaminomethyl) phenyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- [3- [2- (1H-imidazolyl) ethoxy] phenyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- [3-morpholino-5-trifluoromethylphenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (4-pyrrolidino-3-trifluoromethylphenyl) benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (4-piperidino-3-trifluoromethylphenyl) benzamide,

4-methyl-N- [4-morpholino-3-trifluoromethylphenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- (4-ethylamino-3-trifluoromethylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (3-trifluoromethoxyphenyl) benzamide,

N- [4- (2-hydroxypropylamino) -3-trifluoromethylphenyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

N- (4-diethylamino-3-trifluoromethylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- (3-pyridinyl) -5-trifluorophenyl] benzamide,

N- [3- [3- (1H-imidazolyl) propoxy] phenyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (3-pyridinyl) -3-trifluorophenyl] benzamide,

4-methyl-N- [3- (4-methyl-1-piperazinyl) -5-trifluorophenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- [3-methylcarbamoyl-5-trifluorophenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide,

4-methyl-N- [3-methylcarbamoyl-5-morpholino] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide.

The following compounds, which are particularly preferred, are:

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [3- (1H-imidazol-1-yl) propoxy] phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [2- (1H-imidazol-1-yl) ethoxy] phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (ethylamino) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (diethylamino) -3- (trifluoromethyl) phenyl] benzamide,

(±) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4 - [(2-hydroxypropyl) amino] -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- [bis (2-methoxyethyl) amino] -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-methyl-1-piperazinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1-piperidinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1-pyrrolidinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-morpholinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4-phenyl-3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [4- (3-pyridinyl) -3- (trifluoromethyl) phenyl] methyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl ]benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide ,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide ,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- (4-morpholinyl) -5 - [(methylamino) carbonyl] phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3 - [(methylamino) carbonyl] -5- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (3-pyridinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-morpholinyl) -3- (trifluoromethyl) phenyl] benzamide,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide ,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide ,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (5-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide ,

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- (4-methyl-1-piperazinyl) -5- (trifluoromethyl) phenyl] benzamide and

4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl] benzamide.

The invention also relates to 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid and to 3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid ; intermediate compounds to produce preferred amides of the invention.

Particularly, the invention relates to the use of a compound of formula I or its N-oxide or a possible tautomer or pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for treating a disease that is associated with an inhibition of protein kinase activity, wherein the disease is a tumorous disease.

More specifically, the invention relates to the use of a compound of formula I or an N-oxide thereof or a possible tautomer or pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for treating leukemia that is associated with inhibition of Abl tyrosine kinase activity.

The invention further relates to a method for treating a disease that is associated with inhibiting the activity of a protein kinase, which comprises administering a compound of formula I or an N-oxide thereof or a pharmaceutically acceptable salt, wherein the radicals and symbols are as defined above, in an amount effective against the disease a warm-blooded animal in need of such treatment.

The compound according to the invention can be obtained by methods that, although not used to date to obtain new compounds of the present invention, are known, especially a method characterized in that for the synthesis of compounds of formula I, where the symbols R ₁ , R ₂ and R ₄ are as defined for the compound of formula I, 4-R ₄ -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid of formula II

where R ₄ is as defined for a compound of formula I, or a derivative thereof, wherein the -COOH carboxy group is in activated form, reacts with an amine of formula III

where R ₁ and R ₂ are as defined for a compound of formula I, optionally in the presence of a dehydrogenating agent and an inert base and / or a suitable catalyst, and optionally in the presence of an inert solvent;

where the above starting compounds II and III may also be present, if necessary, with functional groups in a protected form and / or in the form of salts, provided that a salt forming group is present and a salt reaction is possible;

any protecting group in the protected derivative of the compound of formula I is removed;

and, if desired, the resulting compound of formula I is converted to another compound of formula I or its N-oxide, the free compound of formula I is converted to a salt, the resulting salt of a compound of formula I is converted to a free compound or other salt, and / or a mixture of isomeric compounds of formula I separated into individual isomers.

Detailed description of the method.

A derivative of a compound of formula II wherein the carboxy group is in activated form is especially a reaction ester, a reaction anhydride or a reaction cyclic amide.

The reaction esters of an acid of formula II are especially esters unsaturated with an attached carbon atom of an ether radical, for example vinyl type esters, such as simple vinyl esters (obtained, for example, by transesterification of the corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl vinyl esters (obtained, for example by treating the corresponding acid with an isoxazoline reagent; 1,2-oxazoline method or Woodward method), or 1-lower alkoxyvinyl esters (obtained, for example, by treatment of the corresponding acid with lower alkoxyacetylene; ethoxyacetylene method), or amidinotype esters such as N, N'-disubstituted amidino esters (obtained, for example, by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example, N, N-dicyclohexylcarbodiimide); carbodiimide or N, N-disubstituted amidino esters (obtained, for example, by treating the corresponding acid with N, N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters, respectively substituted electron acceptors substituents (obtained, for example, by treating the corresponding acid with an appropriate substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyl-diazophenol, in the presence of a condensing an agent such as N, N'-dicyclohexylcarbodiimide; activated aryl ether method), cyanomethyl ethers (obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ether method), thioethers, especially unsubstituted or substituted, for example nitro-substituted, phenylthioesters (obtained, for example, by treating the corresponding acid with unsubstituted or substituted e.g. nitro-substituted thiophenols, inter alia anhydride or carbodiimide method; activated thioesters method), amino or amido ethers (obtained, for example, by the corresponding acid with an N-hydroxyamino or N-hydroxyamide compound, for example, N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenzotriazole, for example, by the anhydride or carbodiimide method; activated N-hydroxy esters) or silyl esters (obtained treating the corresponding acid with a silylating agent, for example hexamethyldisilazane, and reacting with hydroxy groups, but not with amino groups).

The acid anhydrides of formula II may be symmetric or preferably mixed anhydrides of this acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides ( obtained, for example, from the corresponding acid ester through the corresponding hydrazide and its treatment with nitric acid; the azide method), anhydrides with carbon derivatives hydrochloric acid, such as the corresponding esters, for example lower alkyl carboxylic acid half-esters (obtained, for example, by treating the corresponding acid with lower alkyl esters of halogen formic acid, such as chloroformic acid, or 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; method of mixed O-alkylcarboxylic acid anhydrides) or dihalogenated, especially dichlorinated phosphoric acid anhydrides (obtained, for example, by treatment with the corresponding acid is phosphorus oxychloride; phosphorus oxychloride method), or organic acid anhydrides such as mixed organic carboxylic acid anhydrides (obtained, for example, by treating the corresponding acid with an unsubstituted or substituted halide lower alkane or phenylalkanecarboxylic acid, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides), with organic sulfonic acids (obtained, for example, by treating a salt, such as an alkali metal salt, with an appropriate acid, a suitable organic sulfonic acid halide, such as lower alkane or aryl chloride, for example methane or p-toluenesulfonic acid; a mixed sulfonic acid anhydride method), or with organic phosphonic acids (obtained, for example, by treating the corresponding acid with an appropriate organic phosphonic anhydride or phosphonic cyanide; phosphonic acid mixed anhydrides method) and symmetric anhydrides (obtained, for example, by condensation of the corresponding acid in the presence of car bodyimide or 1-diethylaminopropine; symmetric anhydride method).

Suitable cyclic amides are especially amides with five-membered aromatic diazacycles, such as imidazole amides, for example imidazole (obtained, for example, by treating the corresponding acid with N, N'-carbonyldiimidazole; the imidazolidine method) or pyrazoles, for example 3,5-dimethylpyrazole (obtained, e.g. from acid hydrazide by treatment with acetylacetone; pyrazolidine method).

Derivatives of the acids of formula II, where the carboxy group is in activated form, preferably obtained in situ. For example, N, N'-disubstituted amidino esters can be prepared in situ by reaction of a mixture of an acid of formula II and an amine of formula III in the presence of a suitable N, N-disubstituted carbodiimide, for example N, N'-dicyclohexylcarbodiimide. The reaction mixed acid anhydrides of formula II with organic phosphonic acid can be prepared in situ by reaction, for example, with propylphosphonic anhydride or diethyl cyanophosphonate in the presence of a suitable base, preferably a tertiary amine, for example triethylamine or dimethylaminopyridine.

The reaction can be carried out in a known manner, and the reaction conditions will depend especially on whether the carboxy group of the carboxylic acid of formula II is activated, and if so, how, usually in the presence of a suitable solvent or diluent or mixture thereof and, if necessary, in the presence of a condensing an agent which, for example, when the carboxy group is present in the reaction in the form of an anhydride, can also act as an acid binding agent when cooled or heated, for example, in the temperature range from approx. from -30 ° C to about + 150 ° C, especially from about 0 ° C to + 100 ° C, preferably from room temperature (approx. + 20 ° C) to + 70 ° C, in an open or closed reaction vessel and / or in an atmosphere of inert gas, for example nitrogen. Typical condensing agents are, for example, carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazoline compounds, for example 2-ethyl-5-phenyl-1,2-oxazoline 3'-sulfonate and 2-tert-butyl-5-methylisoxazoline perchlorate, or a suitable acylamino compound, for example 2-ethoxy -1-ethoxycarbonyl-1,2-dihydroquinoline. Typical acid-binding condensing agents are, for example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (usually together with sulfate), or organic bases, such as usually pyridine or triethylamine, or sterically hindered trinity alkylamines, for example N , N-diisopropyl-N-ethylamine.

In a preferred embodiment, the carboxylic acid of formula II is reacted with an amine of formula III in a suitable solvent, such as, for example, N, N-dimethylformamide, in the presence of propylphosphonic anhydride or diethyl cyanophosphonate and triethylamine, from 1 to 48 hours between 0 ° C and about 50 ° C, preferably at room temperature.

Protective groups

If one or more functional groups, for example, carboxy, hydroxy, amino or mercapto, are protected or must be protected in the compound of formula III, since they do not participate in the reaction, there are groups that are commonly used in the synthesis of amides, in particular peptide compounds as well as cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars.

Protective groups may already be present in the precursor and protect the functional groups from undesirable side reactions such as acylation, esterification, esterification, oxidation, solvolysis and similar reactions. The characteristic of the protective groups is that they are easy, i.e. without undesirable side reactions, they are removed, usually by solvolysis, reduction, photolysis or also enzymatic activity, for example, under conditions similar to physiological conditions, and that they are not present in the final product. The person skilled in the art knows or can easily determine which protecting groups are suitable for the reactions mentioned hereinafter.

The protection of such functional groups by such protective groups, the protective groups themselves and the reactions for their removal are described, for example, in standard sources of peptide synthesis mentioned earlier and in special sources for protective groups, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Methoden der organischen Chemie (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974 and T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York.

Additional process steps

In additional process steps, if necessary, functional groups of the starting compounds that do not take part in the reaction may be present in unprotected form or may be protected, for example, by one or more protecting groups, referred to as “protecting groups” above. The protecting groups are then wholly or partially removed in accordance with one of the methods described herein.

Salts of compounds of formula I with a salt-forming group can be obtained in a known manner. Acid addition salts of the compounds of formula I can be obtained by treatment with an acid or a suitable anion exchange reagent.

Salts can usually be converted to free compounds, for example, by treatment with suitable basic agents, for example, alkali metal carbonates, alkali metal hydrogen carbonates or alkali metal hydroxides, usually potassium carbonate or sodium hydroxide.

Stoichiometric mixtures, for example mixtures of diastereomers, can be isolated into their corresponding isomers in a known manner by suitable resolution methods. Diastereomeric mixtures, for example, can be isolated into their individual diastereomers by fractional crystallization, chromatography, solvent selection and similar procedures. This separation can take place either for the starting compound or for the compound of formula I directly. Enantiomers can be isolated by the formation of diastereomeric salts, for example, the formation of a salt with enantiomerically pure chiral acid, or chromatography, for example HPLC, using chromatographic substrates with chiral ligands.

A compound of formula I, where R ₁ is hydrogen, can be converted to the corresponding compound, where R ₁ is lower alkyl, by reaction, for example, with a diazonized alkyl compound, especially diazomethane, in an inert solvent, preferably in the presence of a noble metal catalyst, especially in dispersed form, for example copper, or a salt of a noble metal, for example copper (I) chloride or copper (II) sulfate. It is also possible to react with lower alkyl halides or with other lower alkanes carrying a leaving group, for example lower alkyl alcohols esterified with strong organic sulfonic acid, such as lower alkanesulfonic acid (optionally substituted with halogen such as fluorine), aromatic sulfonic acid, for example unsubstituted or substituted benzenesulfonic acid, where the substituents are preferably selected from lower alkyl, such as methyl, halogen, such as bromine and / or nitro, for example, ester with methanesulfonic acid, or p-toluenesulfonic acid. Alkylation takes place under ordinary amide alkylation conditions, especially in aqueous solution and / or in the presence of polar solvents, usually alcohols, for example methanol, ethanol, isopropanol or ethylene glycol, or dipolar aprotic solvents, for example tetrahydrofuran, dioxane or dimethylformamide, where possible the presence of an acidic or basic catalyst, usually at temperatures from about 0 ° C to the boiling point of the corresponding reaction mixture, preferably between 20 ° C and the boiling point I, optionally at elevated pressure, e.g., in a sealed tube, and / or in an inert gas atmosphere, typically nitrogen or argon.

It should be emphasized that reactions corresponding to the transformations mentioned in this section may also occur for the corresponding intermediates.

General process conditions

All process steps described herein can be carried out under known reaction conditions, preferably under the conditions specifically described above, in the absence or usually in the presence of solvents or diluents, preferably those which are inert to the reagents used and capable of dissolving them, in the absence or presence of condensing catalysts agents or neutralizing agents, for example ion exchangers, usually cation exchangers, for example, in the H ⁺ form, depending on the type of reaction and / or reagent for ponies normal, normal or elevated temperature, for example in the range from -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example, from -80 to -60 ° C, at room temperature, at from -20 to 40 ° C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, possibly under pressure, and / or in an inert atmosphere, for example under argon or nitrogen.

Salts may be present in all starting compounds and intermediates if they contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided that they are not destroyed during the reaction.

In all reaction stages, the present isomeric mixtures can be separated into their individual isomers, for example diastereomers or enantiomers, or into any mixtures of isomers, for example racemates or diastereomeric mixtures.

The invention also relates to those forms of the process in which it starts from a compound obtained at any stage as an intermediate, and performs the missing steps, or interrupts the process at any stage, or forms the starting material under reaction conditions, or uses the specified starting material in in the form of a reaction derivative or salt, or produces the resulting compound by the method in accordance with the invention and processes said compound. In a preferred embodiment, each step begins with those starting materials that lead to the compounds described above as preferred, especially as particularly preferred, especially preferred and / or preferred of all of the above.

In a preferred embodiment, the compound of formula I is obtained by the method or analogously to the methods and process steps indicated in the examples.

The compounds of formula I, including their salts, are also obtained in the form of hydrates, or their crystals may include, for example, a solvent used for crystallization (present as a solvate).

Pharmaceutical Formulations, Methods and Applications

The present invention also relates to a method for treating a tumor of the disease that is associated with inhibiting the activity of a protein kinase, which comprises administering a compound of formula I or an N-oxide thereof or a pharmaceutically acceptable salt, wherein the radicals and symbols are as defined above for formula I, in an amount effective for said disease to a warm-blooded animal in need of such treatment.

In particular, the invention relates to a method for treating leukemia, which is associated with inhibiting the activity of Abl tyrosine kinase, which comprises administering a compound of formula I or an N-oxide thereof or a pharmaceutically acceptable salt, wherein the radicals and symbols are as defined above for formula I in an amount effective for the indicated leukemia, a warm-blooded animal in need of such treatment.

The present invention also relates to pharmaceutical compositions which comprise a compound of formula I or its N-oxide as an active ingredient and which can be used especially for the treatment of the diseases mentioned at the beginning. Compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to a warm-blooded animal, especially humans, are particularly preferred. Compositions include the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the disease being treated and on the type, age, weight and individual conditions, individual pharmacokinetic data and route of administration.

The present invention particularly relates to pharmaceutical compositions which comprise a compound of formula I, a tautomer thereof, an N-oxide or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.

The invention also relates to pharmaceutical compositions for use in a method for the prevention or especially therapeutic treatment of a human or animal, to a method for their preparation (especially in the form of compositions for treating tumors) and to a method for treating tumor diseases, especially those mentioned above.

The invention also relates to methods for the use of compounds of formula I or their N-oxides for the preparation of pharmaceutical compositions, which include compounds of formula I or their N-oxides as an active component (active ingredient).

In a preferred embodiment, the pharmaceutical composition is suitable for administration to a warm-blooded animal, especially humans or industrially useful mammals, suffering from a disease associated with inhibition of Abl tyrosine kinase, for example, chronic myelogenous leukemia (CML), and includes an effective amount of a compound of formula I or its N-oxides to inhibit a Bcr-Abl fusion protein, or a pharmaceutically acceptable salt thereof, if salt forming groups are present, together with at least one pharmaceutically acceptable m carrier.

A pharmaceutical composition for the prevention or especially therapeutic treatment of a tumor and other proliferative diseases of a warm-blooded animal, especially a human or an industrially useful mammal, in need of such treatment, especially suffering from such a disease, comprising, as an active ingredient, in an amount that is prophylactically or especially therapeutically active against said diseases, a new compound of formula I or its N-oxides is particularly preferred.

Pharmaceutical compositions comprise from about 1% to about 95% of the active ingredient, single dose administration forms include in a preferred embodiment about 20% to about 90% of the active ingredient, and non-separate dosage forms include in a preferred embodiment about 5% to about 20 % active ingredient. Unit dosage forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Other dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention are prepared in a known manner, for example, by conventional methods of mixing, granulating, coating, dissolving or lyophilizing.

Preference is given to the use of solutions of the active ingredient, as well as suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, which, for example, in the case of lyophilized compositions comprising the active ingredient separately or together with a carrier, can be prepared before use. The pharmaceutical compositions may be sterile and / or may include excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers, and are prepared in a known manner, for example, by conventional dissolution and lyophilization methods. Said solutions or suspensions may include viscosity enhancing agents or solubilizers.

Suspensions in oil include, as an oil, a component of vegetable, synthetic or semi-synthetic oils customary for injection purposes. In this regard, liquid fatty acid esters that contain a long chain fatty acid having from 8 to 22 carbon atoms can be used as an acid component. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is monovalent or polyvalent, for example, mono-, di- or trivalent alcohol, especially glycol and glycerin.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired, grinding the resulting mixture and treating the mixture or granules, if desired or necessary, with the inclusion of additional excipients, in the form of a tablet or tablet core.

Suitable carriers are especially excipients such as sugar, cellulose compositions and / or calcium phosphates, as well as binders such as starch and / or polyvinylpyrrolidone, and / or, if desired, disintegrants. Additional excipients are especially fluid conditioners and lubricants.

Tablet cores may be formulated with suitable, optionally enteric coatings, using concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or a coating solution in suitable organic solvents or solvent mixtures, or to prepare enteric coatings cellulose solution solutions are suitable.

Pharmaceutical compositions for oral administration also include hard gelatin capsules as well as soft, closed capsules consisting of gelatin and a plasticizer. Hard capsules may contain the active ingredient in the form of granules, for example, in admixture with fillers, binders and / or glidants and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, to which stabilizers and detergents can also be added.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories, which consist of a combination of an active ingredient and a suppository base.

For parenteral administration, aqueous solutions of the active ingredient in a water-soluble form, for example, a water-soluble salt, or aqueous injection suspensions, which contain viscosity-enhancing agents, for example sodium carboxymethyl cellulose, sorbitol and / or dextran, and if desired stabilizers, are particularly suitable. The active ingredient, optionally with excipients, may also be in the form of a lyophilisate and may be dissolved before parenteral administration by the addition of suitable solvents.

Solutions that are used, for example, for parenteral administration, can also be used as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.

The invention likewise relates to a process or method for treating one of the aforementioned pathological conditions, especially a disease that is associated with inhibition of tyrosine kinase, especially a corresponding tumor disease. The compounds of formula I or their N-oxides can also be administered, or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the aforementioned diseases, to a warm-blooded animal, for example, a person in need of such treatment. When the patient has a body weight of about 70 kg, the daily administered dose is from about 0.05 g to about 5 g, preferably from about 0.25 g to about 1.5 g of the compound of the present invention.

The present invention particularly relates to the use of a compound of formula I or its N-oxides or its pharmaceutically acceptable salt, especially a compound of formula I, which is considered preferred, or its pharmaceutically acceptable salt, as such or in the form of a pharmaceutical composition with at least one pharmaceutically an acceptable carrier for therapeutic as well as prophylactic administration for one or more of the diseases mentioned above, preferably a disease that is associated with inhibition of otekin kinase, especially a tumor disease, more specifically leukemia, which is associated with inhibition of Abl tyrosine kinase.

The preferred dosage amount, composition and preparation of pharmaceutical formulations (drugs) to be used in each case are described above.

Source materials

New starting materials and / or intermediates, as well as methods for their preparation, are also an object of the invention. In a preferred embodiment, such starting materials and reaction conditions are used to obtain preferred compounds.

The substituted aminobenzoic acid of formula II, for example, can be prepared by reacting an ester of 3-amino-4-R ₄ -benzoic acid, for example 3-amino-4-methylbenzoic acid, with cyanamide and condensing the resulting guanidine with 3- (dimethylamino) -1- (3-pyridinyl) -2-propen-1-one and, finally, hydrolysis of the ether group.

The starting materials of formula III are known, commercially available, or can be prepared analogously or in accordance with methods known in the art.

The following examples serve to illustrate the invention without limiting the scope of the invention.

Abbreviations

DMSO dimethyl sulfoxide HPLC / MS-MS high performance liquid   chromatography / tandem mass spectrometry min minutes t _pl melting temperature Nmp N-methylpyrrolidone NMR nuclear magnetic resonance Peg polyethylene glycol THF tetrahydrofuran

Examples

Example 1: N- (2-Furanylmethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide

A solution containing ~ 50% propylphosphonic anhydride in N, N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~ 1 mmol) was added over 20 minutes to a stirred mixture of 4-methyl-3 - [[4- (3- pyridinyl) -2-pyrimidinyl] amino] benzoic acid (214.4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μl, 0.7 mmol) and triethylamine (776 μl, 5.6 mmol) in 2 ml of N, N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture was treated with a half-saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The crude product was recrystallized from dichloromethane to give the title compound as a crystalline solid.

¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 4.43 (d, 2H); 6.23 (m, 1H); 6.33-6.37 (m, 1H); 7.30 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.53 (m, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.87 (t, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

The starting material was prepared as follows.

Example 1a: 3 - [(Aminoiminomethyl) amino] -4-methylbenzoic Acid Ethyl Mononitrate

Cyanamide (Fluka, Buchs, Switzerland; 77.4 g, 1.842 mol) was added to a solution of 3-amino-4-methylbenzoic acid ethyl ester (J. Med. Chem. 16, 118-122, 1973; 150 g, 0.837 mol) in 850 ml of ethanol. Then hydrochloric acid (Fluka, Buchs, Switzerland; 108 ml 12M, 1.27 mol) was added dropwise over 15 minutes and the reaction mixture was then stirred at 90 ° C (bath temperature) for 15 hours. The solvent was evaporated under reduced pressure to obtain a residue, which was treated with water (1000 ml), and stirred under cooling to 5-10 ° C. A solution of ammonium nitrate (Merck, Darmstadt, Germany; 134.8 g, 1.68 mol) in water (400 ml) was added dropwise over 30 minutes, then ice water (1200 ml). After stirring for an additional 30 minutes, the product was filtered off, washed with ice water (3 × 1000 ml) and dried in air. The residue was washed with diethyl ether (2 × 2000 ml) and dried in vacuo at 50 ° to give the title compound as a crystalline solid, _mp 195-197 ° C.

Example 1b: Ethyl 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl1 amino] benzoic acid

A stirred mixture of the intermediate of Example 1a (164 g, 0.577 mol), 3- (dimethylamino) -1- (3-pyridinyl) -2-propen-1-one (113.8 g, 0.646 mol) and NaOH powder (99 %; Merck, Darmstadt, Germany; 26.6 g, 0.658 mol) in ethanol (2200 ml) was heated under reflux for 68 hours. The reaction solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ) and the solvent was evaporated under reduced pressure to obtain a residue, which was recrystallized from diethyl ether to obtain the title compound as a crystalline solid, _mp 95-96 ° C .

Example 1c: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid

Aqueous sodium hydroxide (500 ml 2M) was added dropwise to a stirred suspension of the intermediate of Example 1b (132.8 g, 0.397 mol) in ethanol (1200 ml) and water (1200 ml). The reaction mixture was stirred at 45 ° C. for 2.5 hours and then treated dropwise with aqueous HCl (1000 ml 1M) for 1.5 hours. After adding water (1000 ml), the precipitate was filtered off, washed with water (4 × 500 ml) and dried at room temperature. The remaining water present in the air-dried product was removed by azeotropic distillation with toluene under reduced pressure. The dried toluene suspension was diluted with diethyl ether and filtered. The remaining solid was washed with diethyl ether and dried in vacuo at 80 ° C to give the title compound, _mp 277-278 ° C.

Example 2: N- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4 - [(4-methyl-1-piperazinyl) methyl] benzeneamine

A solution containing ~ 50% propylphosphonic anhydride in N, N-dimethylformamide (Fluka, Buchs, Switzerland; 875 μl, ~ 1.5 mmol) was added over 20 minutes to a stirred mixture of 4-methyl-3 - [[4- (3 -pyridinyl) -2-pyrimidinyl] amino] benzoic acid (306 mg, 1.0 mmol), 4 - [(4-methyl-1-piperazinyl) methyl] benzolamine (Chem. Abstr. Reg. Number: 70261-82- 4; 205 mg, 1.0 mmol) and triethylamine (830 μl, 6.0 mmol) in 8 ml of N, N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture was treated with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The crude product was recrystallized from ethanol-ethyl acetate to give the title compound as a crystalline solid, _mp 153-155 ° C.

Example 3: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4- (2-pyridinyl) piperazine

A solution containing ~ 50% propylphosphonic anhydride in N, N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~ 1 mmol) was added over 20 minutes to a stirred mixture of 4-methyl-3 - [[4- (3- pyridinyl) -2-pyrimidinyl] amino] benzoic acid (214.4 mg, 0.7 mmol), 1- (2-pyridyl) piperazine (Aldrich, Buchs, Switzerland; 114.3 mg, 0.7 mmol) and triethylamine (776 μl, 5.6 mmol) in 2 ml of N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture was treated with a half-saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The crude product was purified by silica gel column chromatography, eluent 5-10% methanol in dichloromethane, to give the title compound as a solid. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.31 (s, 3H); 3.35-3.74 (m, 8H); 6.65 (ddd, 1H); 6.79 (d, 1H); 7.13 (dd, 1H); 7.32 (d, 1H); 7.44 (d, 1H); 7.49-7.56 (m, 2H); 7.69 (m, 1H); 8.11 (m, 1H); 8.40 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).

The following compounds were prepared analogously using the corresponding amine (shown in parentheses).

Example 4: 4-Methyl-N- [2- (2-pyridinyl) ethyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2- (2-aminoethyl) pyridine ( Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.27 (s, 3H); 2.97 (t, 2H); 3.58 (m, 2H); 7.18 (ddd, 1H); 7.25 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.47-7.56 (m, 2H); 7.65 (m, 1H); 8.06 (d, 1H); 8.39 (m, 1H); 8.44-8.51 (m, 3H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 5: 4-Methyl-N- [1- (phenylmethyl) -4-piperidinyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4-amino-1-benzylpiperidine ( Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.47-1.63 (m, 2H); 1.69-1.80 (m, 2H); 1.92-2.05 (m, 2H); 2.27 (s, 3H); 2.73-2.83 (m, 2H); 3.43 (s, 2H); 3.68-3.83 (m, 1H); 7.18-7.33 (m, 6H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.55 (dd, 1H); 8.10 (m, 1H); 8.14 (d, 1H); 8.37 (m, 1H); 8.49 (d, 1H); 8.65 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).

Example 6: 4-Methyl-N- (4-pyridinylmethyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4- (aminomethyl) pyridine (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.30 (s, 3H); 4.46 (d, 2H); 7.26 (m, 2H); 7.33 (d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.62 (dd, 1H); 8.16 (d, 1H); 8.38 (m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.03 (t, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 7: 4-Methyl-N- [2- (1-methyl-1H-pyrrol-2-yl) ethyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2 - (2-aminoethyl) -1-methylpyrrole [Chem. Abstr. Reg. Number: 83732-75-6]. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 2.75 (t, 2H); 3.42 (m, 2H); 3.51 (s, 3H); 5.76-5.85 (m, 2H); 6.57 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.46-7.58 (m, 2H); 8.10 (br, 1H); 8.40 (m, 1H); 8.48-8.55 (m, 2H); 8.64-8.69 (m, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 8: N - [(4-Methoxyphenyl) methyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4-methoxybenzylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 3.69 (s, 3H); 4.37 (d, 2H); 6.80-6.87 (m, 2H); 7.17-7.23 (m, 2H); 7.31 (d, 1H); 7.42 (d, 1H); 7.47 (ddd, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.87 (t, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 9: 4-Methyl-N- (2-methylpropyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using isobutylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 0.85 (d, 6H); 1.81 (m, 1H); 2.27 (s, 3H); 3.04 (m, 2H); 7.29 (d, 1H); 7.42 (d, 1H); 7.48 (dd, 1H); 7.55 (dd, 1H); 8.07 (d, 1H); 8.31-8.41 (m, 2H); 8.49 (d, 1H); 8.65 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

Example 10: 4-Methyl-N- (2-morpholinoethyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4- (2-aminoethyl) morpholine (Fluka, Buchs, Switzerland ) ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 2.33-2.46 (m, 6H); 3.30-3.40 (m, 2H); 3.53 (m, 4H); 7.30 (d, 1H); 7.42 (d, 1H); 7.46-7.57 (m, 2H); 8.06 (d, 1H); 8.30 (m, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

Example 11: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N - [(tetrahydro-2-furanyl) methyl] benzamide using tetrahydrofurfurylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.49-1.63 (m, 1H); 1.70-1.93 (m, 3H); 2.27 (s, 3H); 3.27 (m, 2H); 3.58 (m, 1H); 3.72 (m, 1H); 3.94 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.56 (dd, 1H); 8.08 (d, 1H); 8.35-8.45 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).

Example 12: N- [2- (2,4-Dihydroxy-5-pyrimidinyl) ethyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 5- ( 2-aminoethyl) -2,4 (1H, 3H) -pyrimidinedione [Chem. Abstr. Reg. Number: 221170-25-8]. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.27 (s, 3H); 2.40 (t, 2H); 3.34 (m, 2H); 7.15 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.47-7.55 (m, 2H); 8.07 (d, 1H); 8.35-8.42 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H); 10.59 (s, 1H); 11.01 (s, 1H).

Example 13: N-Cyclohexyl-4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using cyclohexylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.00-1.16 (m, 1H); 1.18-1.36 (m, 4H); 1.52-1.85 (m, 5H); 2.27 (s, 3H); 3.66-3.82 (m, 1H); 7.28 (d, 1H); 7.41 (d, 1H); 7.48 (m, 1H); 7.55 (dd, 1H); 8.06-8.12 (m, 2H); 8.37 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).

Example 14: N - [(3S) -hexahydro-2-oxo-1H-azepin-3-yl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using L (-) - alpha-amino-epsilon-caprolactam [Chem. Abstr. Reg. Number: 21568-87-6]. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.11-1.31 (m, 1H); 1.37-1.82 (m, 3H); 1.83-1.96 (m, 2H); 2.28 (s, 3H); 3.00-3.13 (m, 1H); 3.15-3.30 (m, 1H); 4.58 (m, 1H); 7.32 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.55 (dd, 1H); 7.84 (m, 1H); 8.08 (d, 1H); 8.13 (d, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.22 (m, 1H).

Example 15: N- [2- (3,4-Dimethoxyphenyl) ethyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2- (3,4- dimethoxyphenyl) ethylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.27 (s, 3H); 2.75 (t, 2H); 3.43 (m, 2H); 3.67 (s, 6H); 6.70 (dd, 1H); 6.77-6.83 (m, 2H); 7.30 (d, 1H); 7.42 (d, 1H); 7.46-7.57 (m, 2H); 8.07 (d, 1H); 8.36-8.46 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

Example 16: Ethyl 2 - [[4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] amino] -4-thiazoleacetic acid using ethyl 2-amino-4-thiazole acetate (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.16 (t, 3H); 2.32 (s, 3H); 3.70 (s, 2H); 4.06 (q, 2H); 7.01 (s, 1H); 7.36 (d, 1H); 7.42-7.54 (m, 2H); 7.82 (d, 1H); 8.34-8.47 (m, 2H); 8.52 (d, 1H); 8.66 (m, 1H); 9.08 (s, 1H); 9.24 (m, 1H); 12.57 (br., 1H).

Example 17: N- [3- (1H-Imidazol-1-yl) propyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 1- (3- aminopropyl) imidazole (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.96 (qui, 2H); 2.30 (s, 3H); 3.24 (m, 2H); 4.01 (t, 2H); 6.91 (s, 1H); 7.22 (m, 1H); 7.34 (d, 1H); 7.45 (d, 1H); 7.51 (ddd, 1H); 7.59 (dd, 1H); 7.70 (s, 1H); 8.14 (d, 1H); 8.42 (m, 1H); 8.47 (t, 1H); 8.52 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.25 (m, 1H).

Example 18: N- (Cyclopropylmethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using cyclohepemethylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 0.17-0.22 (m, 2H); 0.36-0.42 (m, 2H); 0.96-1.06 (m, 1H); 2.28 (s, 3H); 3.11 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 19: N- (2-methoxyethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2-methoxyethylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 3.23 (s, 3H); 3.36-3.46 (m, 4H); 7.31 (d.lH); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.10 (d, 1H); 8.38-8.47 (m, 2H); 8.50 (d, 1H); 8.68 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 20: 4-Methyl-N- [3- (2-oxo-1-pyrrolidinyl) propyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 1- (3- aminopropyl) -2-pyrrolidinone (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.67 (m, 2H); 1.89 (m, 2H); 2.18 (t, 2H); 2.28 (s, 3H); 3.19 (m, 4H); 3.32 (m, 2H); 7.30 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.54 (dd, 1H); 8.09 (d, 1H); 8.31-8.42 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 21: N, 4-Dimethyl-N- (phenylmethyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using N-benzylmethylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 2.86 (s, 3H); 4.51-4.68 (m, 2H); 7.08-7.35 (m, 7H); 7.43 (d, 1H); 7.48 (m, 1H); 7.71 (s, 1H); 8.35-8.54 (m, 2H); 8.67 (m, 1H); 8.97-9.09 (m, 1H); 9.24 (m, 1H).

Example 22: N- [4- (Acetylamino) phenyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4-aminoacetanilide (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.01 (s, 3H); 2.32 (s, 3H); 7.38 (d, 1H); 7.45 (d, 1H); 7.47-7.54 (m, 3H); 7.63-7.71 (m, 3H); 8.22 (m, 1H); 8.43 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 9.90 (s, 1H); 10.11 (s, 1H).

Example 23: N- (4-Methoxy-2-methylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4-methoxy-2-methylaniline (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.16 (s, 3H); 2.32 (s, 3H); 3.73 (s, 3H); 6.75 (dd, 1H); 6.82 (m, 1H); 7.16 (d, 1H); 7.37 (d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (d, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.69 (s, 1H).

Example 24: 4-Methyl-N- [4- (methylsulfonyl) benzyl] -3 - [[4- (3-pyrinyl) -2-pyrimidinyl] amino] benzamide using 4-methylsulfonylbenzylamine hydrochloride (Acros, Morris Plains, NJ ) ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.30 (s, 3H); 3.16 (s, 3H); 4.54 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.55 (m, 2H); 7.63 (dd, 1H); 7.86 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.10 (m, 2H); 9.24 (m, 1H).

Example 25: N - [[4- (Dimethylamino) phenyl] methyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 4- (dimethylamino) benzylamine dihydrochloride ( Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 2.82 (s, 6H); 4.32 (d, 2H); 6.64 (m, 2H); 7.11 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.48 (ddd, 1H); 7.59 (dd, 1H); 8.12 (d, 1H); 8.39 (m, 1H); 8.50 (d, 1H); 8.68 (dd, 1H); 8.81 (t, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 26: N- (2-amino-2-oxoethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using glycinamide hydrochloride (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 3.78 (d, 2H); 7.02 (s, 1H); 7.30-7.36 (m, 2H); 7.44 (d, 1H); 7.53 (ddd, 1H); 7.61 (dd, 1H); 8.11 (m, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.57 (t, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.24 (m, 1H).

Example 27: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] glycine methyl ester using glycine methyl ether hydrochloride (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 3.63 (s, 3H); 3.98 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.52 (ddd, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.87 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).

Example 28: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] beta-alanine methyl ester using beta-alanine methyl ester hydrochloride (Fluka, Buchs, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.27 (s, 3H); 2.57 (t, 2H); 3.46 (m, 2H); 3.57 (s, 3H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50-7.55 (m, 2H); 8.07 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 29: N - [[4- (Aminosulfonyl) phenyl] methyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using p- (aminomethyl) benzenesulfonamide hydrochloride ( Sigma, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 4.51 (d, 2H); 7.30 (s, 2H); 7.34 (d, 1H); 7.43-7.50 (m, 4H); 7.62 (dd, 1H); 7.75 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (t, 1H); 9.09 (s, 1H); 9.24 (m, 1H).

Example 30: N- (3-Hydroxypropyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 3-amino-1-propanol (Aldrich, Buchs, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.65 (qui, 2H); 2.28 (s, 3H); 3.29 (m, 2H); 3.42 (m, 2H); 4.50 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.56 (dd, 1H); 8.09 (d, 1H); 8.36-8.43 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 31: N, N-Diethyl-4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using diethylamine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.04 (m, 6H); 2.28 (s, 3H); 3.31 (m, 4H); 7.02 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.61 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).

Example 32: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] - (L) -phenylalanine 1,1-dimethylethyl ester using tert-butyl ester hydrochloride L phenylalanine (Novabiochem (Juro), Lucerne, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.32 (s, 9H); 2.28 (s, 3H); 3.07 (m, 2H); 4.53 (m, 1H); 7.13-7.29 (m, 5H); 7.32 (d, 1H); 7.44 (d, 1H); 7.50 (ddd, 1H); 7.55 (dd, 1H); 8.05 (m, 1H); 8.39 (m, 1H); 8.49 (d, 1H); 8.63 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 33: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] - (D) -alanine 1,1-dimethylethyl ester using tert-butyl ester hydrochloride D -alanine (Novabiochem (Juro), Lucerne, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.34 (d, 3H); 1.38 (s, 9H); 2.28 (s, 3H); 4.32 (m, 1H); 7.33 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.61 (dd, 1H); 8.14 (m, 1H); 8.40 (m, 1H); 8.50 (m, 1H); 8.58 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 34: N- [1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4-piperidinyl] benzamide using N-4-piperidinylbenzamide (Maybridge Chemical Co . Ltd). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.49 (m, 2H); 1.68-1.94 (m, 2H); 2.30 (s, 3H); 2.92 (m, 1H); 3.16 (m, 1H); 3.79 (m, 1H); 4.05 (m, 1H); 4.42 (m, 1H); 7.08 (dd, 1H); 7.31 (d, 1H); 7.41-7.54 (m, 5H); 7.63 (m, 1H); 7.79-7.84 (m, 2H); 8.28 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).

Example 35: 4- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] morpholine using morpholine (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 3.47 (m, 8H); 7.10 (dd, 1H); 7.30 (d, 1H); 7.44 (m, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.69 (dd, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 36: 1- (4-Methoxyphenyl) -4- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] piperazine using 1- (4-methoxyphenyl) piperazine ( Emka Chemie, Neufahrn, Germany). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.30 (s, 3H); 2.87-3.08 (m, 4H); 3.50-3.75 (m, 4H); 3.67 (s, 3H); 6.78-6.88 (m, 4H); 7.12 (dd, 1H); 7.31 (d, 1H); 7.44 (m, 1H); 7.51 (ddd, 1H); 7.67 (m, 1H); 8.38 (m, 1H); 8.52 (m, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 37: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4- (4-pyridinyl) piperazine using 1- (4-pyridinyl) piperazine ( Emka Chemie, Neufahrn, Germany). H-NMR (400 MHz, DMSO-d ₆ , δ): 2.31 (s, 3H); 3.30 (m, 4H); 3.59 (m, 4H); 6.77 (m, 2H); 7.14 (dd, 1H); 7.32 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.70 (m, 1H); 8.16 (m, 2H); 8.41 (m, 1H); 8.53 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 38: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4- (pyrazinyl) piperazine using 1- (2-pyrazinyl) piperazine (Emka Chemie , Neufahrn, Germany). H-NMR (400 MHz, DMSO-d ₆ , δ): 2.31 (s, 3H); 3.57 (m, 8H); 7.14 (dd, 1H); 7.32 (d, 1H); 7.45 (d, 1H); 7.51 (ddd, 1H); 7.72 (m, 1H); 7.85 (d, 1H); 8.08 (d, 1H); 8.29 (d, 1H); 8.40 (m, 1H); 8.53 (d, 1H); 8.65 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).

Example 39: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4- (phenylmethyl) piperazine using 1-benzylpiperazine (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.21-2.42 (m, 4H); 2.28 (s, 3H); 3.34-3.63 (m, 6H); 7.07 (dd, 1H); 7.21-7.34 (m, 6H); 7.43-7.50 (m, 2H); 7.63 (m, 1H); 8.38 (m, 1H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.03 (s, 1H); 9.22 (m, 1H).

Example 40: 1-Cyclopentyl-4- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] piperazine using 1-cyclopentylpiperazine (Emka Chemie, Neufahrn, Germany). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.20-1.31 (m, 2H); 1.39-1.62 (m, 4H); 1.65-1.75 (m, 2H); 2.18-2.47 (m, 8H); 3.27-3.62 (m, 4H); 7.08 (dd, 1H); 7.29 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.62 (m, 1H); 8.38 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 41: 4 - {{4- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -1-piperazinyl} acetyl} morpholine using 4- [2- ( piperazin-1-yl) acetyl] morpholine (Emka Chemie, Neufahrn, Germany). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 2.31-2.49 (m, 4H); 3.16 (s, 2H); 3.37-3.60 (m, 12H); 7.07 (dd, 1H); 7.29 (d, lH); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.23 (m, 1H).

Example 42: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4- [2-oxo-2- (1-pyrrolidinyl) ethyl] piperazine using 1- [2- (piperazin-1-yl) -acetylpyrrolidine (Emka Chemie, Neufahrn, Germany). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.73 (m, 2H); 1.83 (m, 2H); 2.29 (s, 3H); 2.43 (m, 4H); 3.09 (s, 2H); 3.25 (m, 2H); 3.34-3.63 (m, 6H); 7.07 (dd, 1H); 7.29 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.64 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 43: 4- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -1-piperazinecarboxylic acid ethyl ester using ethyl 1-piperazinecarboxylate (Aldrich, Buchs, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.16 (t, 3H); 2.29 (s, 3H); 3.19-3.63 (m, 8H); 4.02 (q, 2H); 7.10 (dd, 1H); 7.30 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.66 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 44: 2- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -1,2,3,4-tetrahydroisoquinoline using 1,2,3,4- tetrahydroisoquinoline (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.31 (s, 3H); 2.79 (m, 2H); 3.57-3.90 (m, 2H); 4.58-4.79 (m, 2H); 7.08-7.23 (m, 5H); 7.32 (d, 1H); 7.42-7.50 (m, 2H); 7.70 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.05 (s, 1H); 9.24 (m, 1H).

Example 45: N, N-bis (2-Methoxyethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using a bis (2-methoxyethyl) amine (Aldrich, Buchs , Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.28 (s, 3H); 3.09 (br.s, 3H); 3.23 (br.s, 3H); 3.47 (m, 8H); 7.04 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.62 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).

Example 46: 1 '- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -1,4'-bispiperidine using 4-piperidinopiperidine (Aldrich, Buchs, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.21-1.50 (m, 8H); 1.51-1.83 (m, 2H); 2.29 (s, 3H); 2.39 (m, 4H); 2.68 (m, 1H); 2.95 (m, 1H); 3.71 (m, 1H); 4.42 (m, 1H); 7.07 (dd, 1H); 7.28 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.63 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.03 (s, 1H); 9.23 (m, 1H).

Example 47: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -N- (phenylmethyl) glycine ethyl ester using N-benzyl glycine ethyl ester (Fluka, Buchs , Switzerland). ¹ H-NMR (300 MHz, DMSO-d ₆ , δ): 0.97-l, 20 (m, 3H); 2.27 (s, 3H); 3.90-4.12 (m, 4H); 4.58-4.68 (m, 2H); 7.07 (m, 1H); 7.15-7.34 (m, 6H); 7.38-7.53 (m, 2H); 7.65-7.74 (m, 1H); 8.35-8.51 (m, 2H); 8.66 (dd, 1H); 8.96-9.04 (m, 1H); 9.22 (m, 1H).

Example 48: N- (3-Chlorophenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 3-chloroaniline (Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.33 (s, 3H); 7.14 (m, 1H); 7.36 (m, 1H); 7.41 (d, 1H); 7.46 (d, 1H); 7.49 (ddd, 1H); 7.68-7.73 (m, 2H); 7.95 (m, 1H); 8.25 (m, 1H); 8.43 (m, 1H); 8.53 (d, 1H); 8.66 (dd, 1H); 9.15 (s, 1H); 9.26 (m, 1H); 10.33 (s, 1H).

Example 49: N- (2,2-Diphenylethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2,2-diphenylethylamine (Aldrich, Buchs, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.24 (s, 3H); 3.87 (m, 2H); 4.41 (m, 1H); 7.12-7.17 (m, 2H); 7.23-7.31 (m, 9H); 7.41-7.44 (m, 2H); 7.51 (ddd, 1H); 7.97 (m, 1H); 8.37-8.44 (m, 2H); 8.48 (d, 1H); 8.68 (dd, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 50: N- (2,3-Dihydro-1H-inden-1-yl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 1-aminoindane ( Fluka, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.90-2.01 (m, 1H); 2.29 (s, 3H); 2.43 (m, 1H); 2.77-2.86 (m, 1H); 2.91-2.98 (m, 1H); 5.56 (m, 1H); 7.08-7.25 (m, 4H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.64 (dd, 1H); 8.20 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.68-8.72 (m, 2H); 9.08 (s, 1H); 9.24 (m, 1H).

Example 51: N- (Diphenylmethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using alpha-aminodiphenylmethane (Fluka, Buchs, Switzerland) ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 6.41 (d, 1H); 7.20-7.36 (m, 11H); 7.43 (d, 1H); 7.46 (ddd, 1H); 7.67 (dd, 1H); 8.18 (m, 1H); 8.38 (m, 1H); 8.50 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.20 (d, 1H); 9.24 (m, 1H).

Example 52: 4-Methyl-N- [2- (1-piperidinyl) ethyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 1- (2-aminoethyl) piperidine ( Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.30-1.38 (m, 2H); 1.41-1.48 (m, 4H); 2.28 (s, 3H); 2.31-2.41 (m, 6H); 3.33 (m, 2H); 7.31 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.55 (dd, 1H); 8.08 (m, 1H); 8.28 (t, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 53: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- (5,6,7,8-tetrahydro-1-naphthalenyl) benzamide using 5.6, 7.8-tetrahydro-1-naphthylamine (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.63-1.71 (m, 4H); 2.32 (s, 3H); 2.60 (m, 2H); 2.74 (m, 2H); 6.96 dd, 1H); 7.07-7.14 (m, 2H); 7.37 (d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (m, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.65 (br.s).

Example 54: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N - [[4- (trifluoromethyl) phenyl] methyl] benzamide using 4- (trifluoromethyl) benzylamine (Aldrich , Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.30 (s, 3H); 4.53 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.46-7.53 (m, 3H); 7.62 (dd, 1H); 7.66 (m, 2H); 8.16 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.08 (t, 1H); 9.10 (s, 1H); 9.24 (m, 1H).

Example 55: 4-Methyl-N - [(5-methylpyrazinyl) methyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2- (aminomethyl) -5-methylpyrazine (TCI -JP, Distrib. Zürich, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.29 (s, 3H); 2.45 (s, 3H); 4.54 (d, 2H); 7.33 (d, 1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.62 (dd, 1H); 8.14 (m, 1H); 8.40 (m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.07 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).

Example 56: N- (2-Ethoxyethyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2-ethoxyethylamine (TCI-JP, Distrib. Zurich, Switzerland) . ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.07 (t, 3H); 2.28 (s, 3H); 3.30-3.49 (m, 6H); 7.31 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.09 (m, 1H); 8.38-8.45 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 57: 4-Methyl-N- [2- (2-oxo-l-imidazolidinyl) ethyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 1- (2- aminoethyl) imidazolidin-2-one [Chem. Abstr. Reg. Number: 6281-42-1]. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.27 (s, 3H); 3.13-3.22 (m, 4H); 3.30-3.40 (m. 4H); 6.27 (br.s, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.49-7.56 (m, 2H); 8.08 (d, 1H); 8.40 (m, 1H); 8.45 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 58: 4-Methyl-N- (5-methyl-2-pyridinyl) -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2-amino-5-picoline (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.26 (s, 3H); 2.32 (s, 3H); 7.35 (d. 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.64 (dd, 1H); 7.77 (dd, 1H); 8.07 (d, 1H); 8.18 (m, 1H); 8.31 (d, 1H); 8.43 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.08 (s, 1H); 9.25 (m, 1H); 10.58 (s, 1H).

Example 59: 1- [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] -4-phenyl-4-piperidinol using 4-hydroxy-4-phenylpiperidine (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.45-1.73 (m, 2H); 1.88 (m, 2H); 2.28 (s, 3H); 3.15 (m, 1H); 3.47 (m, 1H); 3.64 (m, 1H); 4.39 (m, 1H); 5.14 (s, 1H); 7.14 (dd, 1H); 7.19 (m, 1H); 7.26-7.31 (m, 3H); 7.43 (d, 1H); 7.45-7.51 (m, 3H); 7.69 (d, 1H); 8.40 (m, 1H); 8.48 (d, 1H); 8.67 (dd, 1H); 9.03 (s, 1H); 9.24 (m, 1H).

Example 60: N- (3-Benzoylphenyl) -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 3-aminobenzophenone (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.32 (s, 3H); 7.39 (d, 1H); 7.43-7.58 (m, 6H); 7.67 (m, 1H); 7.70-7.77 (m, 3H); 8.13 (m, 1H); 8.20 (m, 1H); 8.27 (m, 1H); 8.42 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.14 (s, 1H); 9.25 (m, 1H); 10.41 (s, 1H).

Example 61: N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] glycine 1,1-dimethylethyl ester using glycine tert-butyl ester hydrochloride (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.40 (s, 9H); 2.29 (s, 3H); 3.86 (d, 2H); 7.33 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.75 (t, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 62: 4 - [[4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] amino] benzoacetic acid ethyl ester using ethyl 4-aminophenyl acetate (Maybridge Chemical Co. Ltd. ) ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.16 (t, 3H); 2.32 (s, 3H); 3.60 (s, 2H); 4.06 (q, 2H); 7.21 (m, 2H); 7.38 (d, 1H); 7.45 (d, 1H); 7.48 (ddd, 1H); 7.70 (m, 3H); 8.23 (m, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 10.16 (s, 1H).

Example 63: 4-Methyl-N- [3- (methylphenylamino) propyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using N- (3-aminopropyl) -N-methylaniline (TCI-JP, Distrib. Zürich, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.73 (qui, 2H); 2.28 (s, 3H); 2.84 (s, 3H); 3.24-3.37 (m, 4H); 6.55 (m, 1H); 6.65 (m, 2H); 7.10 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.55 (dd, 1H); 8.10 (d, 1H); 8.37-8.44 (m, 2H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 64: Ethyl ester 1 - [[3 - [[4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] amino] phenyl] methyl] -4-piperidinecarboxylic acid using ethyl 1- (3-aminobenzyl) piperidine-4-carboxylate (Maybridge Chemical Co. Ltd.). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.14 (t, 3H); 1.49-1.61 (m, 2H); 1.72-1.80 (m, 2H); 1.92-2.02 (m, 2H); 2.27 (m, 1H); 2.32 (s, 3H); 2.74 (m, 2H); 3.40 (s, 2H); 4.03 (q, 2H); 6.98 (d, 1H); 7.25 (m, 1H); 7.38 (d, 1H); 7.43-7.51 (m, 2H); 7.66-7.73 (m, 3H); 8.25 (s, 1H); 8.42 (m, 1H); 8.52 (d, 1H); 8.65 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 10.14 (s, 1H).

Example 65: [[4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoyl] amino] propanedioic acid diethyl ester using diethylaminomalonate hydrochloride (Aldrich, Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.19 (t, 6H); 2.30 (s, 3H); 4.10-4.22 (m, 4H); 5.27 (d, 1H); 7.35 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.63 (dd, 1H); 8.15 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.11 (s, 1H); 9.21-9.25 (m, 2H).

Example 66: N- [2- [bis (1-Methylethyl) amino] ethyl] -4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide using 2-diisopropylaminoethylamine (Fluka , Buchs, Switzerland). ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 0.95 (m, 12H); 2.28 (s, 3H); 2.49 (m, 2H); 2.94 (m, 2H); 3.17 (m, 2H); 7.30 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.54 (dd, 1H); 8.09 (br.s, 1H); 8.27 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 67: N- [3- (Diethylamino) phenyl1-4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzamide

A solution containing ~ 50% propylphosphonic anhydride in N, N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μl, ~ 1.05 mmol) was added over 20 minutes to a stirred mixture of 4-methyl-3 - [[4- ( 3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (214.4 mg, 0.7 mmol), N, N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μl 5.6 mmol) in 2 ml of N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture was treated with a half-saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was dried in vacuo. The crude product was purified by silica gel chromatography, eluent 2% methanol in dichloromethane, and recrystallized from acetone to give the title compound as a crystalline solid. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).

Example 68: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N - [[3 - [(1-hydroxy-1-methylethyl) 1-5- (1,1 , 1-trifluoromethyl) phenyl] methyl] benzamide

Diethyl cyanophosphonate (Aldrich, Buchs, Switzerland; 0.33 ml, 2.0 mmol) was added to a stirred mixture of 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (306 mg, 1.0 mmol), 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1-trifluoromethyl) benzeneamine (220 mg, 1.0 mmol) and triethylamine (560 μl, 4.0 mmol) in 5 ml of N, N-dimethylformamide at 10 ° C. After stirring for 3 hours at 60 ° C., the mixture was treated with saturated aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined extracts were dried (MgSO ₄ ), filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was recrystallized from ethyl acetate to obtain the title compound as a crystalline solid, _mp 253-258 ° C.

Example 69: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] -N - [(4-methyl-1-piperazinyl) methyl] benzamide

Diethyl cyanophosphonate (Aldrich, Buchs, Switzerland; 0.50 ml, 3.0 mmol) was added to a stirred mixture of 3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid (438 mg, 1.5 mmol ), 4 - [(4-methyl-1-piperazinyl) methyl] benzolamine (308 mg, 1.5 mmol) and triethylamine (840 μl, 3.0 mmol) in 10 ml of N-dimethylformamide at 10 ° C. After stirring for 12 hours at 60 ° C., the mixture was treated with an aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined extracts were washed with water and the solvent was evaporated under reduced pressure to give a residue. The residue was suspended in water and filtered to give a crude product, which was recrystallized from tetrahydrofuran-ethyl acetate to give N- [3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N - [(4-methyl- 1-piperazinyl) methyl] benzamide as a crystalline solid, _mp 220-224 ° C.

Example 69a: 3 - [(Aminoiminomethyl) amino] -4-methylbenzoic acid methyl ester mononitrate

Using the procedure described in example 1a, but with 3-aminobenzoic acid methyl ester (Fluka, Buchs, Switzerland) instead of 3-amino-4-methylbenzoic acid ethyl ester, the title compound was obtained as a crystalline solid, _mp 170- 172 ° C.

Example 69b: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] benzoic acid methyl ester

Using the procedure described in example 1b but with the intermediate of example 69a instead of 4-methyl-3 - [(aminoiminomethyl) amino] -4-methylbenzoic acid ethyl mononitrate, the title compound was obtained as a crystalline solid, _mp 195 -200 ° C.

Example 69c: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] benzoic acid

Using the procedure described in example 1c, but with the intermediate of example 69b, instead of 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid ethyl ester, the title compound was obtained as crystalline solid matter, _mp 285-293 ° C.

Example 70: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] -N - [(3- (1-hydroxy-1-methylethyl) -5- (1,1,1-trifluoromethyl) phenyl ]benzamide

Using the procedure described in example 69, but with 3- (1-hydroxy-1-methylethyl) -5- (1,1,1-trifluoromethyl) benzolamine instead of 4 - [(4-methyl-1-piperazinyl) methyl] benzolamine obtained 3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N - [(3- (1-hydroxy-1-methylethyl) -5- (1,1,1-trifluoromethyl) phenyl] benzamide in the form of a crystalline solid, _mp 213-215 ° C.

Example 71: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [3- (1H-imidazol-1-yl) propoxy] phenyl] benzamide

Using the procedure described in example 3, but using 3- [3- (1H-imidazol-1-yl) propoxy] benzeneamine (Takao Nishi et al., JP 10182459) instead of 1- (2-pyridyl) piperazine, the above was obtained the title compound is in the form of a solid. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.12-2.21 (m, 2H); 2.33 (s, 3H); 3.87 (t, 2H); 4.13 (t, 2H); 6.66 (dd, 1H); 6.87 (s, 1H); 7.15-7.26 (m, 2H); 7.32-7.42 (m, 2H); 7.44-7.52 (m, 3H); 7.61 (s, 1H); 7.70 (d, 1H); 8.24 (s, 1H); 8.43 (d, 1H); 8.53 (d, 1H); 8.67 (d, 1H); 9.13 (s, 1H); 9.26 (br. S, 1H); 10.13 (s, 1H).

Example 72: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [2- (1H-imidazol-1-yl) ethoxy] phenyl] benzamide

Using the procedure described in Example 3, but using 3- [2- (1H-imidazol-1-yl) ethoxy] benzeneamine (Rolf Paul et al. Journal of Medicinal Chemistry (1993), 36 (19), 2716-25 ) instead of 1- (2-pyridyl) piperazine, the title compound was obtained as a crystalline solid. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 2.34 (s, 3H); 4.22 (t, 2H); 4.37 (t, 2H); 6.68 (dd, 1H); 6.90 (s, 1H); 7.21-7.27 (m, 2H); 7.36-7.43 (m, 2H); 7.46-7.53 (m, 3H); 7.67-7.74 (m, 2H); 8.25 (br. S, 1H); 8.44 (dt, 1H); 8.54 (d, 1H); 8.68 (dd, 1H); 9.15 (s, 1H); 9.27 (br. D, 1H); 10.15 (s, 1H).

Example 73: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (ethylamino) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using N-ethyl-2- (trifluoromethyl) -1,4-benzenediamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1-trifluoromethyl ) benzenamine, the title compound is obtained as a crystalline solid, _mp 178-180 ° C.

Aniline was prepared as follows.

Example 73a: N-ethyl-2- (trifluoromethyl) -1,4-benzenediamine

A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) and a solution of ethylamine in ethanol (50 ml 2M, 100 mmol) were heated at 80 ° C for 18 hours in a steel vessel under pressure. The mixture was then cooled and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) to give N-ethyl-4-nitro-6- (trifluoromethyl) benzene as a yellow oil. This product was dissolved in ethanol (180 ml) and hydrogenated at atmospheric pressure over Raney nickel (0.5 g) at 45 ° C. The calculated amount of hydrogen was supplied over 50 hours. The mixture was then filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallized from ether-hexane to give the title compound as a beige crystalline solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.11 (t, 3H), 3.05 (m, 2H), 4.18 (br t, 1H), 4.66 (br.s, 2H), 6.58-6.64 (m, 1H) and 6.68-6.75 (m, 2H).

Example 74: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (diethylamino) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using N, N-diethyl-2- (trifluoromethyl) -1,4-benzenediamine (Toshio Niwa, DE 3524519) instead of 1- (2-pyridyl) piperazine, the title compound was obtained in as a crystalline solid, _mp 128-131 ° C.

Example 75: (±) -4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4 - [(2-hydroxypropyl) amino] -3- (trifluoromethyl) phenyl ]benzamide

Using the procedure described in example 3, but using (±) -1 - [[4-amino-2- (trifluoromethyl) phenyl] amino] -2-propanol (Tsutomu Mano, EP 299497) instead of 1- (2-pyridyl) piperazine, the title compound was obtained as a crystalline solid, _mp 184-186 ° C.

Example 76: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- [bis (2-methoxyethyl) amino] -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using N, N-bis (2-methoxyethyl) -2- (trifluoromethyl) -1,4-benzenediamine (Toshio Niwa, DE 3524519) instead of 1- (2-pyridyl) piperazine, was obtained the title compound as a crystalline solid, _mp 156-157 ° C.

Example 77: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-methyl-1-piperazinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 4- (4-methyl-1-piperazinyl) -3- (trifluoromethyl) benzeneamine (Anthony David Baxter, WO 0119800) instead of 1- (2-pyridyl) piperazine, the title was obtained the compound in the form of a crystalline solid, t _PL 214-217 ° C.

Example 78: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1-piperidinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 4- (1-piperidinyl) -3- (trifluoromethyl) benzeneamine (Leping Li, WO 0151456) instead of 1- (2-pyridyl) piperazine, the title compound was obtained as a crystalline solid substances, _mp 201-202 ° C.

Example 79: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1-pyrrolidinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 4- (1-pyrrolidinyl) -3- (trifluoromethyl) benzeneamine (Steven Lee Bender WO 0153274) instead of 1- (2-pyridyl) piperazine, the title compound was obtained as a crystalline solid substances, _mp 129-130 ° C.

Example 80: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-morpholinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 4- (4-morpholinyl) -3- (trifluoromethyl) benzeneamine (Steven Lee Bender WO 0153274) instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1 , 1,1-trifluoromethyl) benzenamine, the title compound is obtained as a crystalline solid, _mp 216-218 ° C.

Example 81: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4-phenyl-3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 4- (phenyl) -3- (trifluoromethyl) benzeneamine instead of 1- (2-pyridyl) piperazine, the title compound was obtained as a crystalline solid, _mp 172-174 ° C. .

Aniline was prepared as follows.

Example 81a: 4- (Phenyl) -3- (trifluoromethyl) benzeneamine

Phenylboronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and an aqueous solution of potassium carbonate (50 ml 1 M) was added to a stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 ml) and heated at 120 ° C under argon for 1 h. The mixture was then evaporated to dryness under reduced pressure and the residue was treated with water (100 ml) and extracted with ethyl acetate (3 × 80 ml). The combined extracts were washed (brine), dried (MgSO ₄ ), filtered and the solvent was evaporated under reduced pressure to give 4'-nitro-2 '- (trifluoromethyl) - [1,1 ¹ -biphenyl]. Biphenyl was dissolved in ethanol (200 ml) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22 ° C. The calculated amount of hydrogen was supplied over 11 hours. The mixture was then filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by chromatography (silica gel; eluent ethyl acetate) to obtain the title compound as a brown oil. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H ), 7.19-7.23 (m, 2H), and 7.29-7.39 (m, 3H).

Example 82: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- [4- (3-pyridinyl) -3- (trifluoromethyl) phenyl] methyl] benzamide

Using the procedure described in example 69, but using 4- (3-pyridinyl) -3- (trifluoromethyl) benzeneamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1-trifluoromethyl) benzolamine, the title compound was obtained as a crystalline solid, _mp 276-280 ° C.

Aniline was prepared as follows.

Example 82a: 4- (3-Pyridinyl) -3- (trifluoromethyl) benzeneamine

A stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 3.37 g, 12.5 mmol) and 3- (tri-n-butylstannyl) pyridine (Maybridge Chemical Co. Ltd., England; 5.0 g , 13.5 mmol) in xylene (75 ml) was saturated with argon for 10 minutes at 20 ° C. Then tetrakis (triphenylphosphine) palladium (0) (1.4 g, 1.25 mmol) was added and the resulting mixture was heated at 130 ° C for 24 hours under argon atmosphere. The mixture was then cooled, treated with an aqueous solution of sodium hydroxide (150 ml 0.1 M) and saturated with air for 2 hours. The resulting mixture was then diluted with ethyl acetate (200 ml) and filtered. The organic phase was then washed successively with water (2 × 80 ml) and saturated aqueous sodium chloride (1 × 80 ml), dried (MgSO ₄ ), filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 50% ethyl acetate in hexane) to give 3 - [(4-nitro-3- (trifluoromethyl) phenyl] pyridine. This product was dissolved in ethanol (200 ml) and hydrogenated at atmospheric pressure over Raney nickel (0.23 g) at 22 ° C. A calculated amount of hydrogen was supplied within 24 hours. m filtered and the solvent evaporated under reduced pressure to give a crude product which was purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallized from ether-hexane to give the title compound as a colorless crystalline solid, t _mp 92- 93 ° C.

Example 83: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 4- (1H-imidazol-1-yl) -3- (trifluoromethyl) benzeneamine (Steven Lee Bender WO 0153274) instead of 1- (2-pyridyl) piperazine, the title compound was obtained in the form of a crystalline solid, _mp 226-229 ° C.

Example 84: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (2,4-dimethyl-1H-imidazol-1-yl) -3- ( trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5 - (1,1,1-trifluoromethyl) benzenamine, the title compound was obtained as an amorphous solid.

Aniline was prepared as follows.

Example 84a: 4- (2,4-dimethyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzeneamine

A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 6.0 g, 22 mmol) and 2,4-dimethylimidazole (10.6 g, 110 mmol) was heated at 120 ° C for 36 hours under argon atmosphere. The mixture was then cooled and the residue was treated with water (150 ml) and extracted with ethyl acetate (3 × 80 ml). The combined extracts were washed (brine), dried (MgSO ₄ ), filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent ethyl acetate) to obtain 1- [4-nitro-2- (trifluoromethyl) ) phenyl] -1H-imidazole as a yellow crystalline solid. This product was dissolved in ethanol (290 ml) and hydrogenated at atmospheric pressure over Raney nickel (1.15 g) at 25 ° C. The calculated amount of hydrogen was supplied over 14 hours. The mixture was then filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ether-hexane to give the title compound as a crystalline solid, _mp 163-164 ° C.

Example 85: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 4- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- ( 1,1,1-trifluoromethyl) benzenamine, the title compound was obtained as a crystalline solid, _mp 154-163 ° C.

Aniline was prepared as follows.

Example 85a: 4- (4-Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine

Using the procedure described in example 84a, but using 4 (5) -methyl-1H-imidazole instead of 2,4-dimethylimidazole, the title compound was obtained as a beige crystalline solid, _mp 141-143 ° C.

Example 86: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [4- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 4- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- ( 1,1,1-trifluoromethyl) benzenamine, the title compound was obtained as a crystalline solid, _mp 154-163 ° C.

Aniline was prepared as follows.

Example 86a: 4- (2-Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzeneamine

Using the procedure described in example 84a, but using 2-methyl-1H-imidazole instead of 2,4-dimethylimidazole, the title compound was obtained as a colorless crystalline solid, _mp 117-119 ° C.

Example 87: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- (4-morpholinyl) -5 - [(methylamino) carbonyl1 phenyl] benzamide

Using the procedure described in example 69, but using 3-amino-5- (4-morpholinyl) -N- (methyl) benzamide instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1, 1-trifluoromethyl) benzenamine, the title compound was obtained as a crystalline solid, _mp 153-156 ° C.

Aniline was prepared as follows.

Example 87a: 3-Bromo-5-nitrobenzoic acid, 1,1-dimethylethyl ether

A solution of p-butyllithium in hexane (12.8 ml 2.5 M, 32 mmol) was added with stirring to tert-butanol (46 ml) at 25 ° C. under argon. After 30 minutes, the mixture was dropwise treated with a solution of 3-bromo-5-nitrobenzoyl chloride (J. Mindl, Collect. Czech. Chem. Commun. (1973), 38, 3496-505; 32 mmol) in dry THF (40 ml) and stirred for 17 hours. The mixture was then treated with ether (250 ml) and washed with brine. The ether solution was dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) and recrystallized from ether-hexane to give the title compound as a colorless crystalline solid substances, _mp 77-78 ° C.

Example 87b: 3- (4-Morpholinyl) -5-nitrobenzoic acid, 1,1-dimethylethyl ether

A stirred mixture of 3-bromo-5-nitrobenzoic acid, 1,1-dimethylethyl ether (Example 86a; 3.02 g, 10 mmol) and morpholine (1.22 ml, 14 mmol) in toluene (50 ml) was treated with tert-butylate sodium (1.34 g, 14 mmol), tri-tert-butylphosphine (3 ml, 1.5 mmol) and tris- (dibenzylideneacetone) dipalladium [0] (0.45 g, 0.5 mmol) under argon and then heated at 60 ° C for 18 hours. The mixture was diluted with ethyl acetate (150 ml), filtered, washed with brine (2 × 50 ml), dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 15% ethyl acetate in hexane) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless crystalline solid, _mp 116-118 ° C.

Example 87c: 3- (4-Morpholinyl) -5-nitrobenzoic acid, methyl ether

A mixture of 3- (4-morpholinyl) -5-nitrobenzoic acid, 1,1-dimethylethyl ether (Example 87b; 0.77 g, 2.5 mmol), 1,8-diazabicyclo [5.4.0] undec-7 -ene (0.56 ml, 3.75 ml) and potassium bromide (1.09 g, 12.5 mmol) in methanol (25 ml) were stirred at 90 ° C for 250 minutes. Then, the cooled mixture was added to hydrochloric acid (50 ml 0.1 M) and extracted with ethyl acetate (3 × 100 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (2 × 25 ml), water (2 × 25 ml) and brine (2 × 50 ml), dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ethyl acetate-hexane to give the title compound as a yellow crystalline solid.

Example 87d: 3- (4-Morpholinyl) -5-nitro-N- (methyl) benzamide

A stirred solution of 3- (4-morpholinyl) -5-nitrobenzoic acid, methyl ether (Example 86c; 0.53 g, 2 mmol) in toluene (5 ml) was treated with a mixture of methylamine hydrochloride (0.27 g, 4 mmol) under argon atmosphere. ), trimethylaluminum (2 ml of a 2 M solution in toluene, 4 mmol) in toluene (5 ml) and heated at 60 ° C for 18 hours. The cooled mixture was then treated with hydrochloric acid (10 ml of 2 M), stirred for 5 min and then treated with aqueous sodium hydroxide (5 ml of 4 M). The mixture was then treated with water (100 ml) and extracted with ethyl acetate (3 × 100 ml). The combined extracts were washed with brine (2 × 50 ml), dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ethyl acetate to obtain the title compound as a yellow crystalline solid, _mp 204- 207 ° C.

Example 87e: 3-amino-5- (4-morpholinyl) -N- (methyl) benzamide

A solution of 3- (4-morpholinyl) -5-nitro-N- (methyl) benzamide (Example 86d; 300 mg, 1.12 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25 ° C. The calculated amount of hydrogen was supplied over 19 hours. The mixture was then filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ethyl acetate, to obtain the title compound as a beige crystalline solid, _mp 201-204 ° C.

Example 88: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3 - [(methylamino) carbonyl] -5- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 3-amino-5- (trifluoromethyl) -N- (methyl) benzamide instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1- trifluoromethyl) benzenamine gave the title compound as a crystalline solid, _mp 245-249 ° C.

Example 88a: 3-amino-5- (trifluoromethyl) -N- (methyl) benzamide

Using the procedure described in Example 86e, but using α, α, α, trifluoro-N-methyl-5-nitro-m-toluamide (Dean E. Welch, J. Med. Chem. (1969), 12, 299- 303) instead of 3- (4-morpholinyl) -5-nitro-N- (methyl) benzamide, the title compound was obtained as a beige crystalline solid, _mp 113-115 ° C.

Example 89: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (3-pyridinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 5- (3-pyridinyl) -3- (trifluoromethyl) benzeneamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1-trifluoromethyl) benzolamine, the title compound was obtained as a crystalline solid, _mp 275-279 ° C.

Aniline was prepared as follows.

Example 89a: 5- (3-Pyridinyl) -3- (trifluoromethyl) benzeneamine

A stirred solution of 3-amino-5-bromobenzotrifluoride (Apollo, England; 1.12 g, 5 mmol) and 3- (tri-n-butylstannyl) pyridine (Maybridge Chemical Co. Ltd., England; 2.0 g, 5, 4 mmol) in xylene (30 ml) was saturated with argon for 10 minutes at 20 ° C. Then tetrakis (triphenylphosphine) palladium (0) (1.16 g, 1.0 mmol) was added and the resulting mixture was heated at 140 ° C for 36 hours under argon atmosphere. The mixture was then cooled, treated with an aqueous solution of sodium hydroxide (100 ml 0.1 M) and saturated with air for 2 hours. The resulting mixture was then diluted with ethyl acetate (200 ml) and filtered. The organic phase was then washed successively with water (2 × 80 ml) and saturated aqueous sodium chloride (1 × 80 ml), dried (MgSO ₄ ), filtered and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent ethyl acetate) to give the title compound as a brown oil. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 5.73 (br s, 2H), 6.83 (dd, 1H), 6.99 (d, 1H), 7.04 (d, 1H), 7.39 (dd, 1H), 7.64 (d, 1H), 8.42 (m, 1H) and 8.53 (dd, 1H).

Example 90: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-morpholinyl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 5- (4-morpholinyl) -3- (trifluoromethyl) benzeneamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1,1-trifluoromethyl) benzolamine, the title compound was obtained as a crystalline solid, _mp 208-211 ° C.

Aniline was prepared as follows.

Example 90a: [3-Bromo-5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

A mixture of 3-amino-5-bromobenzotrifluoride (Apollo, England; 12 g, 50 mmol), di-tert-butyl dicarbonate (12 g, 55 mmol) and 4-dimethylaminopyridine (0.61 g, 5 mmol) in acetonitrile (100 ml ) was stirred at 60 ° C for 8 hours. The solvent was then evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 10% ethyl acetate in hexane) and recrystallized from hexane to obtain the title compound as a colorless crystalline solid matter, _mp 113-115 ° C.

Example 90b: [3- (4-Morpholinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

Using the procedure described in example 86b, but using [3-bromo-5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (Example 90a) instead of 3-bromo-5-nitrobenzoic acid, 1,1-dimethylethyl ether, the title compound is obtained as a crystalline solid, _mp 146-148 ° C.

Example 90c: 5- (4-Morpholinyl) -3- (trifluoromethyl) benzeneamine

[3- (4-Morpholinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (Example 90b; 1.7 g, 5 mmol) was treated with a solution of hydrogen chloride in isopropanol (30 ml 4 M) and heated at 60 ° C for 5 hours. The solvent was evaporated under reduced pressure and the residue was treated with an aqueous solution of sodium bicarbonate (80 ml) and extracted with ethyl acetate (3 × 80 ml). The combined extracts were washed with brine (2 × 50 ml), dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ether-hexane to obtain the title compound as a yellow crystalline solid, t _mp 96-97 ° C.

Example 91: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 5- (2-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- ( 1,1,1-trifluoromethyl) benzenamine, the title compound was obtained as a crystalline solid, _mp 242-247 ° C.

Aniline was prepared as follows.

Example 91a: 3- (2-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile

A mixture of 3-fluoro-5- (trifluoromethyl) benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 mmol) in N, N-dimethylacetamide (80 ml ) was stirred at 145 ° C for 19 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with brine (200 ml), dried (Na ₂ SO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by recrystallization from ether-hexane to give the title compound as a yellow crystalline solid, _mp 132-134 ° C.

Example 91b: 3- (2-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid

A solution of 3- (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile (example 91a; 16.7 g, 66 mmol) in dioxane (300 ml) was added to an aqueous solution of sodium hydroxide (275 ml 1 M) and the mixture was heated at 95 ° C for 18 h. The solvent was evaporated under reduced pressure and the residue was neutralized with hydrochloric acid (1 M) and extracted with butanol (2 × 250 ml). The solvent was evaporated under reduced pressure to obtain the title compound. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ): 7.17 (s, 1H); 8.03 (s, 1H); 8.12 (s, 1H); 8.35 (s, 1H); 8.41 (s, 1H); 8.53 (s, 1H); 13.90 (br., 1H).

Example 91c: [3- (2-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

Triethylamine (5.23 ml, 37.5 mmol) was added to a stirred suspension of 3- (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid (Example 91b; 6.8 g, 25 mmol ) in tert-butanol (200 ml). Diphenylphosphoryl azide (7.6 g, 27.5 mmol) was added to the resulting solution, and the mixture was heated at 80 ° C for 16 hours. The solvent was evaporated under reduced pressure and the residue was treated with water (100 ml) and extracted with ethyl acetate (2 × 100 ml). . The combined extracts were washed with brine (100 ml), dried (Na ₂ SO ₄ ) and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, eluent 2% ethanol in ethyl acetate) and recrystallized from ether-hexane with obtaining the title compound as a colorless crystalline solid, _mp 203-208 ° C.

Example 91d: 5- (2-Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzeneamine

Using the procedure described in example 90c, but using [3- (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (example 91c) instead of [3 - (4-morpholinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether, the title compound was obtained as a yellow crystalline solid, _mp 130-133 ° C.

Example 92: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- ( 1,1,1-trifluoromethyl) benzenamine gave the title compound as a crystalline solid, _mp 235-236 ° C.

Aniline was prepared as follows.

Example 92a: 3- (4-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile

Using the procedure described in example 91a, but using 4-methyl-1H-imidazole instead of 2-methylimidazole, the title compound was obtained as a crystalline solid, _mp 127-128 ° C.

Example 92b: 3- (4-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid

Using the procedure described in example 91b, but using 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile (example 92a) instead of 3- (2-methyl-1H-imidazole-1- il) -5- (trifluoromethyl) benzonitrile, the title compound was obtained as a crystalline solid, _mp > 300 ° C.

Example 92c: [3- (4-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

Using the procedure described in example 91c, but using 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid (example 92b) instead of 3- (2-methyl-1H-imidazole-1 -yl) -5- (trifluoromethyl) benzoic acid, the title compound is obtained as a crystalline solid, _mp 186-188 ° C.

Example 92d: 5- (2-Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzeneamine

Using the procedure described in example 91d, but using [3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (example 92c) instead of [3 - (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether, the title compound was obtained as a colorless crystalline solid, _mp 127-131 ° FROM.

Example 93: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (5-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 5- (5-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of 1- (2-pyridyl) piperazine, the title compound was obtained as crystalline solid matter, _mp 231-233 ° C.

Aniline was prepared as follows.

Example 93a: 3- (5-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile

Using the procedure described in example 91a, but using 4-methyl-1H-imidazole instead of 2-methylimidazole, the title compound was obtained as a crystalline solid, _mp 99-101 ° C.

Example 93b: 3- (5-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid

Using the procedure described in example 91b, but using 3- (5-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzonitrile (example 93a) instead of 3- (2-methyl-1H-imidazole-1- il) -5- (trifluoromethyl) benzonitrile, the title compound was obtained as a colorless crystalline solid, _mp 243-245 ° C.

Example 93c: [3- (5-Methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

Using the procedure described in example 91c, but using 3- (5-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoic acid (example 93b) instead of 3- (2-methyl-1H-imidazole-1 -yl) -5- (trifluoromethyl) benzoic acid, the title compound is obtained as a crystalline solid, _mp 169-171 ° C.

Example 93d: 5- (5-Methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine

Using the procedure described in example 91d, but using [3- (5-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (example 93c) instead of [3 - (2-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether, the title compound was obtained as a colorless crystalline solid, _mp 131-133 ° FROM.

Example 94: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [3- (4-methyl-1-piperazinyl) -5- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 69, but using 3- (4-methyl-1-piperazinyl) -5- (trifluoromethyl) benzeneamine instead of 3 - [(1-hydroxy-1-methylethyl)] - 5- (1,1, 1-trifluoromethyl) benzenamine, the title compound was obtained as a crystalline solid, _mp 192-194 ° C.

Aniline was prepared as follows.

Example 94a: [3- (4-Methyl-1-piperazinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether

Using the procedure described in example 87b, but using 1-methyl-1-piperazine instead of morpholine, the title compound was obtained as a crystalline solid, _mp 225 ° C.

Example 94b: 3- (4-Methyl-1-piperazinyl) -5- (trifluoromethyl) benzeneamine

Using the procedure described in example 90c, but using [3- (4-methyl-1-piperazinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether (example 94a) instead of [3- (4- morpholinyl) -5- (trifluoromethyl) phenyl] carboxylic acid, 1,1-dimethylethyl ether, the title compound was obtained as an oil. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 2.20 (s, 3H), 2.42 (m, 4H), 3.07 (m, 4H), 3.32 (br s, 2H) 5.34 (s, 1H); and 6.31 (s, 2H).

Example 95: 4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [2- (1-pyrrolidinyl) -5- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 3, but using 2- (1-pyrrolidinyl) -5- (trifluoromethyl) benzeneamine (Lancaster Synthesis Ltd .; Yasuhiro Ohtake et al. WO 9965874) instead of 1- (2-pyridyl) piperazine, the above was obtained in the title compound as a crystalline solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.77-1.82 (m, 4H); 2.34 (s, 3H); 3.31-3.37 (m, 4H); 6.86 (d, 1H); 7.34-7.44 (m, 2H); 7.47 (d, 1H); 7.49-7.53 (m, 1H); 7.73 (dd, 1H); 8.27 (d, 1H); 8.43 (dt, 1H); 8.53 (d, 1H); 8.69 (dd, 1H); 9.13 (s, 1H); 9.27 (d, 1H); 9.96 (s, 1H).

Example 96: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl] benzamide

Using the procedure described in example 1, but using 3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid instead of 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl ] amino] benzoic acid and 5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) benzolamine instead of furfurylamine, the title compound was obtained as a pale yellow crystalline solid, _mp 264-266 ° C.

Example 96a: 3 - [(Aminoiminomethyl) amino] benzoic acid ethyl mononitrate

Using the procedure described in Example 1, but using 3-aminobenzoic acid ethyl ester (Fluka, Buchs, Switzerland) instead of 3-amino-4-methylbenzoic acid ethyl ester, the title compound was obtained as a crystalline solid, _mp 170- 172 ° C.

Example 96b: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] benzoic acid ethyl ester

Using the procedure described in Example 1b, but using 3 - [((aminoiminomethyl) amino] benzoic acid ethyl mononitrate instead of 3 - [((aminoiminomethyl) amino] -4-methylbenzoic acid ethyl mononitrate), the title compound was obtained as a crystalline solid substances, _mp 197-199 ° C.

Example 96c: 3 - [[4- (3-Pyridinyl) -2-pyrimidinyl] amino] benzoic acid

Using the procedure described in example 1c, but using 3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] benzoic acid ethyl ester instead of 4-methyl-3 - [[4- (3-pyridinyl) ethyl ester -2-pyrimidinyl] amino] benzoic acid, the title compound is obtained as a crystalline solid, _mp 291-295 ° C.

Example 97: Soft Capsules

5000 soft gelatin capsules, each of which includes as an active ingredient 0.05 g of one of the compounds of formula I mentioned in the examples above, was prepared as follows:

250 g of the crushed active ingredient was suspended in 2 L of Lauroglykol® (propylene glycol laurate, Gattefbssé S. A., Saint Priest, France) and placed in a wet atomizer to obtain particles of about 1 to 3 μm in size. 0.419 g of the mixture was then placed in soft gelatin capsules using a capsule filling device.

Example 98: Pharmacokinetic data

A test compound of formula I was formulated for administration to female OF1 mice from IFACREDO, France, first dissolving in N-methylpyrrolidone (NMP) and then diluting PEG300 to a final concentration of 10% v / v. NMP: 90% v / v PEG300, obtaining a pure solution of the compound. Concentrations were adjusted to introduce a constant volume of 10 ml / kg body weight. The compound was obtained immediately before use. The formulated compound was administered orally with a gastric tube to provide doses of 50 mg / kg. At specific time points, mice (4 at each time) were anesthetized with 3% isoflurane in medical oxygen and blood samples were taken by cardiac puncture in heparinized tubes (approximately 30 IU / ml). The animals were then sacrificed without recovery from anesthesia. Plasma was obtained from blood by centrifugation (10,000 g, 5 min) and analyzed immediately or stored frozen at -70 ° C.

Plasma samples (10-250 μl), for example, were destroyed using 5 μl of an internal standard mixed with 200 μl of 0.1 M NaOH and 500 μl of chloroform in an 1.5 ml Eppendorf tube and shaken thoroughly for 10 minutes with an Eppendorf mixer . The mixture was then centrifuged (3 min at 10'000 × rpm), the organic phase was transferred to a second Eppendorf tube and evaporated to dryness in a vacuum centrifuge (Speedvac 5301). The dry residue, for example, was dissolved in 250 μl of 10% v / v. acetonitrile in water containing 0.1% formic acid. Subsequent analysis was performed, for example, by high performance liquid chromatography / tandem mass spectrometry (HPLC / MS-MS) using an Agilent 1100 Series HPLC system (Agilent, Palo Alto, CA, USA) with a vacuum degasser, a dual pump and a thermostatic column compartment connected with auto sample cooling system (HTS PAL, CTC Analytics, Zwingen, Switzerland). A sample (5-15 μl) was applied, for example, to an Ultra Phenyl column (particle size 3 μm, 50 × 1 mm; Restek, Bellefonte, USA) with a protective column (4 × 2 mm) of the same material (Phenomenex, Torrance, USA). After equilibration, for example, with water and a latent period of 1 min, the sample was eluted, for example, by a linear gradient of 0-100% acetonitrile in water containing 0.2% v / v. formic acid for 11 min at a flow rate of 60 μl / min. A column was obtained for the next sample, for example, by equilibrating it for 3 minutes with 100% water to its original positions. Separation was carried out, for example, at a column temperature of 40 ° C. The column flow was injected, for example, directly into a triple stage ion source of a quadropole mass spectrometer (Quattro Ultima ™, Micromass, Manchester, UK) controlled by Masslynx ™ 3.5 software (Micromass, Manchester, UK), using as an ionization method electrospray ionizing positive device (ESI +). The compound was determined using MS / MS followed by fragmentation of the incoming ions. The limitation of xanthanation was determined, for example, at 0.002 nmol / L. Calibration curves were constructed from known amounts of the compound, including a fixed amount of the internal standard in plasma treated as described above. The concentration of unknown samples was calculated from the ratio of the area under the peak of the selected daughter ion of the analytical sample for its internal standard product (ordinate axis) versus the nominal concentration (abscissa axis). Regression analysis was performed using Quanlynx ™ software, Masslynx ™ 3.5 (Micromass, Manchester, UK).

Example 99: In vitro Inhibition Data

In vitro enzymatic (c-Abl, KDR, Flt3) inhibition data are expressed as% inhibition at 10 μM. Measurements were performed as described above in the general description.

Example Abl% @ 10 μM KDR% @ 10 μM Flt 3% @ 10 μM one 51 57 2 97 73 3 66 71 four 77 46 5 71 60 6 51 56 7 72 45 8 70 81 9 44 39 10 57 48 eleven 53 41 12 22 33 13 78 48 fourteen 49 54 fifteen 60 23 16 42 10 17 54 62 eighteen 56 62 19 41 33 twenty 56 22 21 thirty 93 22 59 7 23 90 67 24 80 70 25 44 73 26 55 56 27 54 51 28 73 61 29th 78 thirty 57 37 31 68 83 32 90 37 33 97 51 34 73 89 35 27 47 36 57 77

Example Abl% @ 10 μM KDR% @ 10 μM Flt 3% @ 10 μM 41 13 52 42 32 56 43 37 63 44 75 97 45 34 61 46 one 43 47 39 74 48 90 fifty 49 72 37 fifty 87 83 51 92 52 52 78 37 53 88 79 54 69 74 55 43 54 56 40 44 57 8 42 58 40 26 59 75 83 60 79 36 61 95 65 62 59 44 63 74 82 64 56 59 65 96 60 66 67 23 67 98 88 41 68 99 96

Claims (5)

1. The compound of the formula

where R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl;
R2 is lower alkyl substituted with one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl (indane), benzcyclohexyl, a five-, six- or seven-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen and oxygen which may be unsaturated or fully saturated and is unsubstituted or substituted with lower alkyl, phenyl lower alkyl or oxo; phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxycarbonylpiperidino lower alkyl, N-lower alkylpiperazino lower alkyl, lower alkoxycarbonyl lower alkyl, lower alkoxy, 1H-imidazolyl-lower lower alkoxycarbonyl, lower alkylcarbamoyl, amino, mono- or disubstituted with lower alkyl, morpholino, lower alkylsulfonyl, halogen and benzoyl; and
R3 is hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, N-monophenylcarbamoyl, mono- or disubstituted with lower alkyl or lower alkoxy amino, cyclopropyl, a five- or six-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen and oxygen which may be unsaturated or fully or partially saturated and is unsubstituted or substituted with lower alkyl, phenyl lower alkyl or oxo; phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkoxy, sulfamoyl, lower alkylsulfonyl; a monocyclic heteroaryl group comprising two nitrogen atoms in the ring and zero oxygen atoms selected from imidazolyl, pyrazinyl and furanyl, where they are unsubstituted; or where
R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted with lower alkyl; a six-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen, which may be unsaturated or fully saturated and unsubstituted or substituted with lower alkyl, hydroxy, pyridyl, pyrazinyl or pyrimidinyl; oxaalkylene with one oxygen atom and three or four carbon atoms or azaalkylene with one nitrogen atom and three or four carbon atoms, where nitrogen is unsubstituted or substituted by lower alkyl, phenyl lower alkyl, substituted by lower alkoxy phenyl, pyridinyl or pyrazinyl;
R4 represents hydrogen or lower alkyl;
moreover, R2 does not mean 3-aminopropyl, if R1 and R4 represents hydrogen, and the prefix "lower" means a radical having inclusively up to 7 carbon atoms,
or a pharmaceutically acceptable salt of such a compound. 2. The compound of formula I according to claim 1, where
R1 represents hydrogen, lower alkyl, lower alkoxy lower alkyl;
R2 is lower alkyl substituted with one or two identical or different radicals R3, benzcyclopentyl (indane), benzocyclohexyl, cyclohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxoazepinyl, oxazepinyl, phenyl, phenyl substituted with one or two substituents selected from the group consisting of lower alkyl, lower alkoxycarbonylpiperidino lower alkyl, N-lower alkylpiperazino lower alkyl, 1H-imidazolyl lower alkoxy, lower alkoxycarbonyl, izshy alkylcarbamoyl, amino, mono- or disubstituted by lower alkyl, morpholino, halogen, and benzoyl; and
R3 is hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-monophenylcarbamoyl, a five- or six-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen and oxygen, which may be unsaturated or fully or partially saturated and is unsubstituted or substituted with lower alkyl, phenyl-lower alkyl or oxo, phenyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of lower alkoxy, sulfam yl, lower alkylsulfonyl; phenyl, pyridyl, halogen and benzoyl; a monocyclic heteroaryl group comprising one or two nitrogen atoms selected from imidazolyl, benzimidazolyl, pyrazinyl and furanyl, or where
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted with lower alkyl; a six-membered heterocyclic system with one or two heteroatoms selected from the group consisting of nitrogen, which may be unsaturated or fully saturated and unsubstituted or substituted with lower alkyl, hydroxy, pyridyl, pyrazinyl or pyrimidinyl; oxaalkylene with one oxygen atom and four carbon atoms or azaalkylene with one nitrogen atom and four carbon atoms, where the nitrogen is unsubstituted or substituted lower alkyl, phenyl lower alkyl, pyridinyl or pyrazinyl;
R4 represents hydrogen or lower alkyl;
wherein R2 does not mean 3-aminopropyl if R1 and R4 are hydrogen, and the prefix "lower" means a radical having up to 7 carbon atoms, or a pharmaceutically acceptable salt of such a compound. 3. The method of obtaining the compounds of formula I according to claim 1

or a pharmaceutically acceptable salt, wherein the symbols R1, R2 and R4 are as defined in claim 1, wherein the compound of formula II

where R4 is as defined for a compound of formula I, or a derivative thereof, wherein the -COOH carboxy group is in activated form, is reacted with an amine of formula III

where R1 and R2 are as defined for a compound of formula I, optionally in the presence of a dehydrogenating agent and an inert base and optionally in the presence of an inert solvent;
where the above starting compounds II and III may also be present with protected functional groups, optionally and / or in the form of salts, provided that there is a salt-forming group and the reaction is possible in the form of a salt;
any protecting group in the protected derivative of the compound of formula I is removed;
and, if necessary, the free compound of formula I is converted into a pharmaceutically acceptable salt, the resulting pharmaceutically acceptable salt of a compound of formula I is converted to a free compound or other pharmaceutically acceptable salt. 4. A pharmaceutical composition that inhibits protein kinase activity, comprising, as an active ingredient, a compound of formula I according to any one of claims 1 and 2, or a pharmaceutically acceptable salt in an effective amount together with a pharmaceutically acceptable carrier. 5. A method of treating a disease that is associated with an inhibition of protein kinase activity, which comprises administering a compound of formula I according to any one of claims 1 or 2, or a pharmaceutically acceptable salt.